Nitrogen substituted biaryl purine derivatives as potent antiproliferative agents

ABSTRACT

The compounds of the present invention are 2,6,9-trisubstituted purine derivatives which are inhibitors of cyclin/cdk complexes. The compounds of the current invention also are potent inhibitors of human cellular proliferation. As such, the compounds of the present invention constitute pharmaceutical compositions with a pharmaceutically acceptable carrier. Such compounds are useful in treating a disorder mediated by elevated levels of cell proliferation in a mammal compared to a healthy mammal by administering to such mammal an effective amount of the compound. Examples of the compounds of the present invention are represented by the following chemical structures:  
                 
 
     with X, Y, D, Q, V, A, R 1 , R 2 , R 3 , R 4 , and n 1  defined herein.

FIELD OF THE INVENTION

[0001] The present invention relates to compounds that are shown to bepotent cyclin/cyclin dependent kinase (cdk) inhibitors. Compounds withthese properties are shown to be potent inhibitors of cell growth andproliferation. Such compounds can be used to treat the followingconditions in mammals: rheumatoid arthritis, lupus, type 1 diabetes,multiple sclerosis, cancer, restenosis, gout and other proliferativediseases involving elevated levels of cell proliferation compared tohealthy mammals.

[0002] Compounds of the present invention which are biaryl substitutedpurine derivatives are shown to be potent antiproliferative agentsagainst a number of human transformed cell lines, and also inhibitors ofhuman cyclin/cdk kinase complexes.

BACKGROUND OF THE INVENTION

[0003] Cellular Proliferation and Cancer.

[0004] The disruption of external or internal regulation of cellulargrowth can lead to uncontrolled proliferation and in cancer, tumorformation. This loss of control can occur at many levels and, indeed,does occur at multiple levels in most tumors. Further, although tumorcells can no longer control their own proliferation, they still must usethe same basic cellular machinery employed by normal cells to drivetheir growth and replication.

[0005] Cyclin Dependent Kinases and Cell Cycle Regulation.

[0006] Progression of the normal cell cycle from the G1 to S phase, andfrom the G2 phase to M phase is dependent on cdks (Sherr, C. J., Science274:1672-1677 (1996)). Like other kinases, cdks regulate molecularevents in the cell by facilitating the transfer of the terminalphosphate of adenosine triphosphate (ATP) to a substrate protein.Isolated cdks require association with a second subunit, called cyclins(Desai et al., Mol. Cell. Biol., 15:345-350 (1995)). Cyclins causeconformational changes at the cdk active site, allowing ATP access andinteraction with the substrate protein. The balance between its rates ofsynthesis and degradation controls the level of each cyclin at any pointin the cycle (Elledge, S. J., et al., Biochim. Biophys. Acta,1377:M61-M70 (1998)). The influences of cyclin/cdk activity on the cellcycle and cellular transformation are summarized in Table 1.

[0007] Abnormal Cyclin/cdk Activity in Cancer.

[0008] In a normal cell, interlocking pathways respond to the cell'sexternal environment and internal checkpoints monitor conditions withinthe cell to control the activity of cyclin/cdk complexes. A reasonablehypothesis is that the disruption of normal control of cyclin/cdkactivity may result in uncontrolled proliferation. This hypothesisappears to hold in a number of tumor types in which cyclins areexpressed at elevated levels (Table 1). Mutations in the genes encodingnegative regulators (proteins) of cyclin/cdk activity are also found intumors (Larsen, C. -J., Prog. Cell Cycle Res., 3:109-124 (1997)); (Kamb,A., Trends in Genetics, 11:136-140 (1995)). Members of the Cip family ofcdk inhibitors form a ternary complex with the cyclin/cdk and requirebinding to cyclinA, cycline, or cyclinD (Hall, M., et al., Oncogene,11:1581-1588 (1995)). In contrast, Ink family members form a binarycomplex with cdk4 or cdk6 and prevent binding to cyclinD (Parry, D.; etal., EMBO J., 14:503-511 (1995)). TABLE 1 Associations Among Cyclins andCancers Cell Cycle Cyclin Role Associated cdk Cancer A S, G2 cdk1, cdk2hepatocellular carcinoma (Wang, J.; et to M al., Oncogene, 8:1653-1656(1992)) B1/B2 G2 cdk1 none yet defined to M D1 G1 cdk4, cdk6 parathyroidadenoma (Motokura, T., et al., Nature, 350:512-515 (1991)) centrocytic Bcell lymphoma (Withers, D. A., et al., Mol. Cell. Biol., 11:4846- 4853(1991)) esophageal carcinoma (Jiang, W., et al., Cancer Res.,52:2980-2983 (1992)) breast cancer (Dickson, C., et al., Cancer Lett.,90:43-50 (1995)) squamous cell carcinoma (Bartkova, J., et al., CancerRes., 55:949-956 (1995)) hepatocellular carcinoma (Nishida, N., et al.,Cancer Res., 54:3107-3110 (1994)) D2 G1 cdk4, cdk6 colorectal carcinoma(Leach, F. S., et al., Cancer Res., 53:1986-1989 (1993)) E G1 cdk2breast cancer (Keytomarsi, K., et al., to S Cancer Res., 54:380-385(1994)) gastric carcinoma (Akama, Y.; et al., Jap. J. Cancer Res.,86:617-621 (1995)) colorectal carcinoma (Kitihara, K.; et al., Int. J.Cancer, 62:25-28 (1995))

[0009] Inhibitors of Cyclin/cdk Complexes as Potential AnticancerAgents.

[0010] Tumors with elevated cyclin/cdk activity, whether from the overexpression of cyclins or the loss of an endogenous cdk inhibitor, areprime targets for potential therapies based on small molecule cyclin/cdkinhibitors. In fact, several small molecule inhibitors of cyclin/cdksare reported (Meijer, L., et al., “Progress in Cell Cycle Research,”Plenum Press: New York, 351-363 (1995)) and appear to bind at the ATPsite of the kinase. Some information is known about small moleculeinhibitors of other kinases, such as PKC (serine kinase) (Murray, K. J.et al., “Ann. Rep. Med. Chem.,” J. Bristol, Ed., Academic Press, Inc.:New York, Chapter 26 (1994)) and tyrosine kinases (Fantl, W. J., et al.,Ann. Rev. Biochem., 62:453 (1993); Burke, T. R., Drugs of the Future,17:119-1131 (1992); Dobrusin, E. M. et al., “Ann. Rep. Med. Chem,” J.Bristol, Ed., Academic Press, Inc.: New York, Chapter 18 (1992); Spence,P., Curr. Opin. Ther. Patents, 3:3 (1993)). A number of known inhibitorswere obtained from commercial sources or were synthesized by literatureprocedures.

[0011] Purine Compounds as Cyclin/cdk Inhibitors.

[0012] There are several reports of 2,6-diamino substituted purinederivatives as cyclin/cdk inhibitors and as inhibitors of cellularproliferation. Among those are reports by U.S. Pat. No. 5,583,137 toCoe, et al., olomoucine (Vesely, J., et al., Eur. J. Biochem.,224:771-786 (1994)), roscovitine (Meijer, L., Eur. J. Biochem.,243:527-536 (1997)), WO 97/16452 to Zimmerman, Imbach, P., et al.,Bioorg. Med. Chem. Lett., 9:91-96 (1999), Norman, T. C., et al., J.Amer. Chem. Soc., 118:7430-7431 (1996), Gray, N. S., et al., TetrahedronLett., 38:1161-1164 (1997), Gray, N. S., et al., Science, 281:533-538(1998), WO 98/05335 to Lum, et al., Schow, S. R., et al., Bioorg. Med.Chem. Lett, 7:2697-2702 (1997), U.S. Pat. No., 5,886,702 to Mackman, etal., Nugiel, D. A., et al., J. Org. Chem., 62:201-203 (1997), andFiorini, M. T. et al., Tetrahedron Lett., 39:1827-1830 (1998). Many ofthese reported compounds are shown to inhibit cyclin/cdk complexes andhave modest cellular proliferation inhibition properties.

[0013] The compounds of the present invention are shown to have farsuperior biological activities as cyclin/cdk complex inhibitors as wellas inhibitors of cellular proliferation compared to those previouslyreported. In fact, the art (e.g., Fiorini, M. T. et al., TetrahedronLett, 39:1827-1830 (1998)) teaches away from compounds of thisinvention, claiming lack of cellular proliferation inhibition.

SUMMARY OF THE INVENTION

[0014] The compounds of the present invention are 2,6,9-trisubstitutedpurine derivatives which are inhibitors of cyclin/cdk complexes. Thecompounds of the current invention also are potent inhibitors of humancellular proliferation. As such, the compounds of the present inventionconstitute pharmaceutical compositions with a pharmaceuticallyacceptable carrier. Such compounds are useful in treating conditions ina mammal mediated by elevated levels of cell proliferation compared to ahealthy mammal by administering to such mammal an effective amount ofthe compound.

[0015] In one embodiment, the compounds of the present invention arerepresented by the chemical structure found in Formula I

[0016] wherein:

[0017] R₁ are the same or different and independently selected from thegroup consisting of:

[0018] H;

[0019] C₁-C₆-straight chain alkyl;

[0020] C₂-C₆-straight alkenyl chain;

[0021] C₃-C₆-branched alkyl chain;

[0022] C₃-C₆-branched alkenyl chain;

[0023] C₃-C₇-cycloalkyl;

[0024] CH₂—(C₃-C₇-cycloalkyl);

[0025] CH₂CF₃;

[0026] CH₂CH₂CF₃; and

[0027] CH(CF₃)₂;

[0028] the combination of X, D, and Q are either:

[0029] D=Q=N, and X=CH; or

[0030] D=X=N, and Q=CH; or

[0031] Q=X=N, and D=CH; or

[0032] Q=N, and D=X=CH;

[0033] V=NH;

[0034] O;

[0035] S; or

[0036] CH₂;

[0037] R₂=phenyl;

[0038] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from the group consistingof R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl,Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH;

[0039] 1-naphthyl;

[0040] 2-naphthyl;

[0041] heterocycles selected from the group consisting of:

[0042] 2-pyridyl;

[0043] 3-pyridyl;

[0044] 4-pyridyl;

[0045] 2-pyrimidyl;

[0046] 4-pyrimidyl;

[0047] 5-pyrimidyl;

[0048] thiophene-2-yl;

[0049] thiophene-3-yl;

[0050] 2-furanyl;

[0051] 3-furanyl;

[0052] oxazol-2-yl;

[0053] oxazol-4-yl;

[0054] oxazol-5-yl;

[0055] thiazol-2-yl;

[0056] thiazol-4-yl;

[0057] thiazol-5-yl;

[0058] imidazol-2-yl;

[0059] imidazol-4-yl;

[0060] pyrazol-3-yl;

[0061] pyrazol-4-yl;

[0062] isoxazol-3-yl;

[0063] isoxazol-4-yl;

[0064] isoxazol-5-yl;

[0065] isothiazol-3-yl;

[0066] isothiazol-4-yl;

[0067] isothiazol-5-yl;

[0068] 1,3,4-thiadiazol-2-yl;

[0069] benzo[b]furan-2-yl;

[0070] benzo[b]thiophene-2-yl;

[0071] 2-pyrrolyl;

[0072] 3-pyrrolyl;

[0073] 1,3,5-triazin-2-yl;

[0074] pyrazin-2-yl;

[0075] pyridazin-3-yl;

[0076] pyridazin-4-yl;

[0077] 2-quinolinyl;

[0078] 3-quinolinyl;

[0079] 4-quinolinyl;

[0080] 1-isoquinolinyl;

[0081] 3-isoquinolinyl; and

[0082] 4-isoquinolinyl; or

[0083] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from the groupconsisting of Br, Cl, F, R₁, and C(O)CH₃;

[0084] R₃ are the same or different and independently selected from thegroup consisting of:

[0085] H;

[0086] C₁-C₄-straight chain alkyl;

[0087] C₃-C₄-branched chain alkyl;

[0088] C₂-C₄-alkenyl chain;

[0089] (CH₂)_(n)Ph; and

[0090] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0091] R₄=H;

[0092] C₁-C₄-straight chain alkyl; or

[0093] C₃-C₄-branched chain alkyl;

[0094] R₃ and R₄ can be linked together by a carbon chain to form withintervening atoms a 5-8-membered saturated or unsaturated ring;

[0095] n₁=0-3;

[0096] n=0-3;

[0097] A=CH₂;

[0098] (CH₂)₂;

[0099] (CH₂)₃;

[0100] OCH₂CH₂; or

[0101] CHCH₃;

[0102] Y=H;

[0103] OR₁;

[0104] N(R₁)₂;

[0105] N(R₁)C(O)R₃;

[0106] N(R₁)C(O)R₅;

[0107] N(R₁)C(O)CH(R₆)NH₂;

[0108] N(R₁)SO₂R₃;

[0109] N(R₁)C(O)NHR₃; or

[0110] N(R₁)C(O)OR₆;

[0111] R₅=C₃-C₇-cycloalkyl;

[0112] R₆=C₁-C₄-straight chain alkyl;

[0113] C₃-C₄-branched chain alkyl;

[0114] C₂-C₄-alkenyl chain;

[0115] (CH₂)_(n)Ph; or

[0116] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0117] or a pharmaceutically acceptable salt thereof.

[0118] Another aspect of the present invention is directed to a compoundof the following formula:

[0119] wherein:

[0120] R₁ are the same or different and independently selected from thegroup consisting of:

[0121] H;

[0122] C₁-C₆-straight chain alkyl;

[0123] C₂-C₆-straight alkenyl chain;

[0124] C₃-C₆-branched alkyl chain;

[0125] C₃-C₆-branched alkenyl chain;

[0126] C₃-C₇-cycloalkyl;

[0127] CH₂—(C₃-C₇-cycloalkyl);

[0128] CH₂CF₃;

[0129] CH₂CH₂CF₃; and

[0130] CH(CF₃)₂;

[0131] the combination of X, D, and Q are either:

[0132] D=Q=N, and X=CH; or

[0133] D=X=N, and Q=CH; or

[0134] Q=X=N, and D=CH; or

[0135] Q=N, and D=X=CH;

[0136] V=NH;

[0137] O;

[0138] S; or

[0139] CH₂;

[0140] R₂=phenyl;

[0141] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from the group consistingof R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl,Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH;

[0142] 1-naphthyl;

[0143] 2-naphthyl;

[0144] heterocycles selected from the group consisting of:

[0145] 2-pyridyl;

[0146] 3-pyridyl;

[0147] 4-pyridyl;

[0148] 2-pyrimidyl;

[0149] 4-pyrimidyl;

[0150] 5-pyrimidyl;

[0151] thiophene-2-yl;

[0152] thiophene-3-yl;

[0153] 2-furanyl;

[0154] 3-furanyl;

[0155] oxazol-2-yl;

[0156] oxazol-4-yl;

[0157] oxazol-5-yl;

[0158] thiazol-2-yl;

[0159] thiazol-4-yl;

[0160] thiazol-5-yl;

[0161] imidazol-2-yl;

[0162] imidazol-4-yl;

[0163] pyrazol-3-yl;

[0164] pyrazol-4-yl;

[0165] isoxazol-3-yl;

[0166] isoxazol-4-yl;

[0167] isoxazol-5-yl;

[0168] isothiazol-3-yl;

[0169] isothiazol-4-yl;

[0170] isothiazol-5-yl;

[0171] 1,3,4-thiadiazol-2-yl;

[0172] benzo[b]furan-2-yl;

[0173] benzo[b]thiophene-2-yl;

[0174] 2-pyrrolyl;

[0175] 3-pyrrolyl;

[0176] 1,3,5-triazin-2-yl;

[0177] pyrazin-2-yl;

[0178] pyridazin-3-yl;

[0179] pyridazin-4-yl;

[0180] 2-quinolinyl;

[0181] 3-quinolinyl;

[0182] 4-quinolinyl;

[0183] 1-isoquinolinyl;

[0184] 3-isoquinolinyl; and

[0185] 4-isoquinolinyl; or

[0186] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from the groupconsisting of Br, Cl, F, R₁, and C(O)CH₃;

[0187] n=0-3;

[0188] A=CH₂;

[0189] (CH₂)₂;

[0190] (CH₂)₃;

[0191] OCH₂CH₂; or

[0192] CHCH₃;

[0193] Y=H;

[0194] OR₁;

[0195] N(R₁)₂;

[0196] N(R₁)C(O)R₃;

[0197] N(R₁)C(O)R₅;

[0198] N(R₁)C(O)CH(R₆)NH₂;

[0199] N(R₁)SO₂R₃;

[0200] N(R₁)C(O)NHR₃; or

[0201] N(R₁)C(O)OR₆;

[0202] R₃ are the same or different and independently selected from thegroup consisting of:

[0203] H;

[0204] C₁-C₄-straight chain alkyl;

[0205] C₃-C₄-branched chain alkyl;

[0206] C₂-C₄-alkenyl chain;

[0207] (CH₂)_(n)Ph; and

[0208] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0209] R₅=C₃-C₇-cycloalkyl;

[0210] R₆=C₁-C₄-straight chain alkyl;

[0211] C₃-C₄-branched chain alkyl; or

[0212] C₂-C₄-alkenyl chain;

[0213] or a pharmaceutically acceptable salt thereof.

[0214] The present invention is also directed to a process forpreparation of a purine derivative compound of the formula:

[0215] wherein:

[0216] R₁ are the same or different and independently selected from thegroup consisting of:

[0217] H;

[0218] C₁-C₆-straight chain alkyl;

[0219] C₂-C₆-straight alkenyl chain;

[0220] C₃-C₆-branched alkyl chain;

[0221] C₃-C₆-branched alkenyl chain;

[0222] C₃-C₇-cycloalkyl;

[0223] CH₂—(C₃-C₇-cycloalkyl);

[0224] CH₂CF₃;

[0225] CH₂CH₂CF₃; and

[0226] CH(CF₃)₂;

[0227] the combination of X, D, and Q are either:

[0228] D=Q=N, and X=CH; or

[0229] D=X=N, and Q=CH; or

[0230] Q=X=N, and D=CH; or

[0231] Q=N, and D=X=CH;

[0232] V=NH;

[0233] O;

[0234] S; or

[0235] CH₂;

[0236] R₂=phenyl;

[0237] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from the group consistingof R₁, OR₁, SR₁S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl,Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH;

[0238] 1-naphthyl;

[0239] 2-naphthyl;

[0240] heterocycles selected from the group consisting of:

[0241] 2-pyridyl;

[0242] 3-pyridyl;

[0243] 4-pyridyl;

[0244] 2-pyrimidyl;

[0245] 4-pyrimidyl;

[0246] 5-pyrimidyl;

[0247] thiophene-2-yl;

[0248] thiophene-3-yl;

[0249] 2-furanyl;

[0250] 3-furanyl;

[0251] oxazol-2-yl;

[0252] oxazol-4-yl;

[0253] oxazol-5-yl;

[0254] thiazol-2-yl;

[0255] thiazol-4-yl;

[0256] thiazol-5-yl;

[0257] imidazol-2-yl;

[0258] imidazol-4-yl;

[0259] pyrazol-3-yl;

[0260] pyrazol-4-yl;

[0261] isoxazol-3-yl;

[0262] isoxazol-4-yl;

[0263] isoxazol-5-yl;

[0264] isothiazol-3-yl;

[0265] isothiazol-4-yl;

[0266] isothiazol-5-yl;

[0267] 1,3,4-thiadiazol-2-yl;

[0268] benzo[b]furan-2-yl;

[0269] benzo[b]thiophene-2-yl;

[0270] 2-pyrrolyl;

[0271] 3-pyrrolyl;

[0272] 1,3,5-triazin-2-yl;

[0273] pyrazin-2-yl;

[0274] pyridazin-3-yl;

[0275] pyridazin-4-yl;

[0276] 2-quinolinyl;

[0277] 3-quinolinyl;

[0278] 4-quinolinyl;

[0279] 1-isoquinolinyl;

[0280] 3-isoquinolinyl; and

[0281] 4-isoquinolinyl; or

[0282] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from the groupconsisting of Br, Cl, F, R₁, and C(O)CH₃;

[0283] R₃ are the same or different and independently selected from thegroug consisting of:

[0284] H;

[0285] C₁-C₄-straight chain alkyl;

[0286] C₃-C₄-branched chain alkyl;

[0287] C₂-C₄-alkenyl chain;

[0288] (CH₂)_(n)Ph; and

[0289] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0290] R₄=H;

[0291] C₁-C₄-straight chain alkyl; or

[0292] C₃-C₄-branched chain alkyl;

[0293] R₃ and R₄ can be linked together by a carbon chain to form withintervening atoms a 5-8-membered saturated or unsaturated ring;

[0294] n₁=0-3;

[0295] n=0-3;

[0296] A=CH₂;

[0297] (CH₂)₂;

[0298] (CH₂)₃;

[0299] OCH₂CH₂; or

[0300] CHCH₃;

[0301] Y=H;

[0302] N(R₁)₂;

[0303] N(R₁)C(O)R₃;

[0304] N(R₁)C(O)R₅;

[0305] N(R₁)C(O)CH(R₆)NH₂;

[0306] N(R₁)SO₂R₃;

[0307] N(R₁)C(O)NHR₃; or

[0308] N(R₁)C(O)OR₆;

[0309] R₅=C₃-C₇-cycloalkyl;

[0310] R₆=C₁-C₄-straight chain alkyl;

[0311] C₃-C₄-branched chain alkyl;

[0312] C₂-C₄-alkenyl chain;

[0313] (CH₂)_(n)Ph; or

[0314] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0315] or a pharmaceutically acceptable salt thereof, said processcomprising:

[0316] reacting a first intermediate compound of the formula:

[0317] where Z=Br or I

[0318] with a compound of the formula: R₂—B(OH)₂, R₂—Sn(n-Bu)₃, orR₂—Sn(Me)₃, or mixtures thereof, under conditions effective to form thepurine derivative compound.

[0319] Another aspect of the present invention is directed to a processfor preparation of a purine derivative compound of the formula:

[0320] wherein:

[0321] R₁ are the same or different and independently selected from thegroup consisting of:

[0322] H;

[0323] C₁-C₆-straight chain alkyl;

[0324] C₂-C₆-straight alkenyl chain;

[0325] C₃-C₆-branched alkyl chain;

[0326] C₃-C₆-branched alkenyl chain;

[0327] C₃-C₇-cycloalkyl;

[0328] CH₂—(C₃-C₇-cycloalkyl);

[0329] CH₂CF₃;

[0330] CH₂CH₂CF₃; and

[0331] CH(CF₃)₂;

[0332] the combination of X, D, and Q are either:

[0333] D=Q=N, and X=CH; or

[0334] D=X=N, and Q=CH; or

[0335] Q=X=N, and D=CH; or

[0336] Q=N, and D=X=CH;

[0337] V=NH;

[0338] O;

[0339] S; or

[0340] CH₂;

[0341] R₂=phenyl;

[0342] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from the group consistingof R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl,Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH;

[0343] 1-naphthyl;

[0344] 2-naphthyl;

[0345] heterocycles selected from the group consisting of:

[0346] 2-pyridyl;

[0347] 3-pyridyl;

[0348] 4-pyridyl;

[0349] 2-pyrimidyl;

[0350] 4-pyrimidyl;

[0351] 5-pyrimidyl;

[0352] thiophene-2-yl;

[0353] thiophene-3-yl;

[0354] 2-furanyl;

[0355] 3-furanyl;

[0356] oxazol-2-yl;

[0357] oxazol-4-yl;

[0358] oxazol-5-yl;

[0359] thiazol-2-yl;

[0360] thiazol-4-yl;

[0361] thiazol-5-yl;

[0362] imidazol-2-yl;

[0363] imidazol-4-yl;

[0364] pyrazol-3-yl;

[0365] pyrazol-4-yl;

[0366] isoxazol-3-yl;

[0367] isoxazol-4-yl;

[0368] isoxazol-5-yl;

[0369] isothiazol-3-yl;

[0370] isothiazol-4-yl;

[0371] isothiazol-5-yl;

[0372] 1,3,4-thiadiazol-2-yl;

[0373] benzo[b]furan-2-yl;

[0374] benzo[b]thiophene-2-yl;

[0375] 2-pyrrolyl;

[0376] 3-pyrrolyl;

[0377] 1,3,5-triazin-2-yl;

[0378] pyrazin-2-yl;

[0379] pyridazin-3-yl;

[0380] pyridazin-4-yl;

[0381] 2-quinolinyl;

[0382] 3-quinolinyl;

[0383] 4-quinolinyl;

[0384] 1-isoquinolinyl;

[0385] 3-isoquinolinyl; and

[0386] 4-isoquinolinyl; or

[0387] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from the groupconsisting of Br, Cl, F, R₁, and C(O)CH₃;

[0388] R₃ are the same or different and independently selected from thegroup consisting of:

[0389] H;

[0390] C₁-C₄-straight chain alkyl;

[0391] C₃-C₄-branched chain alkyl;

[0392] C₂-C₄-alkenyl chain;

[0393] (CH₂)_(n)Ph; and

[0394] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0395] R₄=H;

[0396] C₁-C₄-straight chain alkyl; or

[0397] C₃-C₄-branched chain alkyl;

[0398] R₃ and R₄ can be linked together by a carbon chain to form withintervening atoms a 5-8-membered saturated or unsaturated ring;

[0399] n₁=0-3;

[0400] n=0-3;

[0401] A=CH₂;

[0402] (CH₂)₂;

[0403] (CH₂)₃;

[0404] OCH₂CH₂; or

[0405] CHCH₃;

[0406] Y=H;

[0407] OR₁;

[0408] N(R₁)₂;

[0409] N(R₁)C(O)R₃;

[0410] N(R₁)C(O)R₅;

[0411] N(R₁)C(O)CH(R₆)NH₂;

[0412] N(R₁)SO₂R₃;

[0413] N(R₁)C(O)NHR₃; or

[0414] N(R₁)C(O)OR₆;

[0415] R₅=C₃-C₇-cycloalkyl;

[0416] R₆=C₁-C₄-straight chain alkyl;

[0417] C₃-C₄-branched chain alkyl;

[0418] C₂-C₄-alkenyl chain;

[0419] (CH₂)_(n)Ph; or

[0420] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0421] or a pharmaceutically acceptable salt thereof, said processcomprising: reacting a first intermediate compound of the formula:

[0422] under reductive or hydrogenation conditions effective to form thepurine derivative compound.

[0423] Another aspect of the present invention is directed to a processfor preparation of a purine derivative compound of the formula:

[0424] wherein:

[0425] R₁ are the same or different and independently selected from thegroup consisting of: H;

[0426] C₁-C₆-straight chain alkyl;

[0427] C₂-C₆-straight alkenyl chain;

[0428] C₃-C₆-branched alkyl chain;

[0429] C₃-C₆-branched alkenyl chain;

[0430] C₃-C₇-cycloalkyl;

[0431] CH₂—(C₃-C₇-cycloalkyl);

[0432] CH₂CF₃;

[0433] CH₂CH₂CF₃; and

[0434] CH(CF₃)₂;

[0435] the combination of X, D, and Q are either:

[0436] D=Q=N, and X=CH; or

[0437] D=X=N, and Q=CH; or

[0438] Q=X=N, and D=CH; or

[0439] Q=N, and D=X=CH;

[0440] V=NH;

[0441] O;

[0442] S; or

[0443] CH₂;

[0444] R₂=phenyl;

[0445] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from the group consistingof R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl,Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH;

[0446] 1-naphthyl;

[0447] 2-naphthyl;

[0448] heterocycles selected from the group consisting of:

[0449] 2-pyridyl;

[0450] 3-pyridyl;

[0451] 4-pyridyl;

[0452] 2-pyrimidyl;

[0453] 4-pyrimidyl;

[0454] 5-pyrimidyl;

[0455] thiophene-2-yl;

[0456] thiophene-3-yl;

[0457] 2-furanyl;

[0458] 3-furanyl;

[0459] oxazol-2-yl;

[0460] oxazol-4-yl;

[0461] oxazol-5-yl;

[0462] thiazol-2-yl;

[0463] thiazol-4-yl;

[0464] thiazol-5-yl;

[0465] imidazol-2-yl;

[0466] imidazol-4-yl;

[0467] pyrazol-3-yl;

[0468] pyrazol-4-yl;

[0469] isoxazol-3-yl;

[0470] isoxazol-4-yl;

[0471] isoxazol-5-yl;

[0472] isothiazol-3-yl;

[0473] isothiazol-4-yl;

[0474] isothiazol-5-yl;

[0475] 1,3,4-thiadiazol-2-yl;

[0476] benzo[b]furan-2-yl;

[0477] benzo[b]thiophene-2-yl;

[0478] 2-pyrrolyl;

[0479] 3-pyrrolyl;

[0480] 1,3,5-triazin-2-yl;

[0481] pyrazin-2-yl;

[0482] pyridazin-3-yl;

[0483] pyridazin-4-yl;

[0484] 2-quinolinyl;

[0485] 3-quinolinyl;

[0486] 4-quinolinyl;

[0487] 1-isoquinolinyl;

[0488] 3-isoquinolinyl; and

[0489] 4-isoquinolinyl; or

[0490] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from the groupconsisting of Br, Cl, F, R₁, and C(O)CH₃;

[0491] R₃ are the same or different and independently selected from thegroup consisting of:

[0492] H;

[0493] C₁-C₄-straight chain alkyl;

[0494] C₃-C₄-branched chain alkyl;

[0495] C₂-C₄-alkenyl chain;

[0496] (CH₂)_(n)Ph; and

[0497] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0498] R₄=H;

[0499] C₁-C₄-straight chain alkyl; or

[0500] C₃-C₄-branched chain alkyl;

[0501] R₃ and R₄ can be linked together by a carbon chain to form withintervening atoms a 5-8-membered saturated or unsaturated ring;

[0502] n₁=0-3;

[0503] n=0-3;

[0504] A=CH₂;

[0505] (CH₂)₂;

[0506] (CH₂)₃;

[0507] OCH₂CH₂; or

[0508] CHCH₃;

[0509] Y=H;

[0510] OR₁;

[0511] N(R₁)₂;

[0512] N(R₁)C(O)R₃;

[0513] N(R₁)C(O)R₅;

[0514] N(R₁)C(O)CH(R₆)NH₂;

[0515] N(R₁)SO₂R₃;

[0516] N(R₁)C(O)NHR₃; or

[0517] N(R₁)C(O)OR₆;

[0518] R₅=C₃-C₇-cycloalkyl;

[0519] R₆=C₁-C₄-straight chain alkyl;

[0520] C₃-C₄-branched chain alkyl;

[0521] C₂-C₄-alkenyl chain;

[0522] (CH₂)_(n)Ph; or

[0523] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0524] or a pharmaceutically acceptable salt thereof, said processcomprising:

[0525] reacting a first intermediate compound of the formula:

[0526] with a compound of the formula:

[0527] where V₁=NH₂;

[0528] OH; or

[0529] SH;

[0530] under conditions effective to form the purine derivativecompound.

[0531] Another aspect of the present invention is directed to a processfor preparation of a purine derivative compound of the formula:

[0532] wherein:

[0533] R₁ are the same or different and independently selected from thegroup consisting of:

[0534] H;

[0535] C₁-C₆-straight chain alkyl;

[0536] C₂-C₆-straight alkenyl chain;

[0537] C₃-C₆-branched alkyl chain;

[0538] C₃-C₆-branched alkenyl chain;

[0539] C₃-C₇-cycloalkyl;

[0540] CH₂—(C₃-C₇-cycloalkyl);

[0541] CH₂CF₃;

[0542] CH₂CH₂CF₃; and

[0543] CH(CF₃)₂;

[0544] the combination of X, D, and Q are either:

[0545] D=Q=N and X=CH; or

[0546] D=X=N and Q=CH; or

[0547] Q=X=N and D=CH; or

[0548] Q=N and D=X=CH;

[0549] V=NH;

[0550] O;

[0551] S; or

[0552] CH₂;

[0553] R₂=phenyl;

[0554] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from the group consistingof R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl,Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH;

[0555] 1-naphthyl;

[0556] 2-naphthyl;

[0557] heterocycles selected from the group consisting of:

[0558] 2-pyridyl;

[0559] 3-pyridyl;

[0560] 4-pyridyl;

[0561] 2-pyrimidyl;

[0562] 4-pyrimidyl;

[0563] 5-pyrimidyl;

[0564] thiophene-2-yl;

[0565] thiophene-3-yl;

[0566] 2-furanyl;

[0567] 3-furanyl;

[0568] oxazol-2-yl;

[0569] oxazol-4-yl;

[0570] oxazol-5-yl;

[0571] thiazol-2-yl;

[0572] thiazol-4-yl;

[0573] thiazol-5-yl;

[0574] imidazol-2-yl;

[0575] imidazol-4-yl;

[0576] pyrazol-3-yl;

[0577] pyrazol-4-yl;

[0578] isoxazol-3-yl;

[0579] isoxazol-4-yl;

[0580] isoxazol-5-yl;

[0581] isothiazol-3-yl;

[0582] isothiazol-4-yl;

[0583] isothiazol-5-yl;

[0584] 1,3,4-thiadiazol-2-yl;

[0585] benzo[b]furan-2-yl;

[0586] benzo[b]thiophene-2-yl;

[0587] 2-pyrrolyl;

[0588] 3-pyrrolyl;

[0589] 1,3,5-triazin-2-yl;

[0590] pyrazin-2-yl;

[0591] pyridazin-3-yl;

[0592] pyridazin-4-yl;

[0593] 2-quinolinyl;

[0594] 3-quinolinyl;

[0595] 4-quinolinyl;

[0596] 1-isoquinolinyl;

[0597] 3-isoquinolinyl; and

[0598] 4-isoquinolinyl; or

[0599] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from the groupconsisting of Br, Cl, F, R₁, and C(O)CH₃;

[0600] R₃ are the same or different and independently selected from thegroup consisting of:

[0601] C₁-C₄-straight chain alkyl;

[0602] C₃-C₄-branched chain alkyl;

[0603] C₂-C₄-alkenyl chain;

[0604] (CH₂)_(n)Ph; and

[0605] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0606] R₄=H;

[0607] C₁-C₄-straight chain alkyl; or

[0608] C₃-C₄-branched chain alkyl;

[0609] R₃ and R₄ can be linked together by a carbon chain to form withintervening atoms a 5-8-membered saturated or unsaturated ring;

[0610] n₁=0-3;

[0611] n=0-3;

[0612] A=CH₂;

[0613] (CH₂)₂;

[0614] (CH₂)₃;

[0615] OCH₂CH₂; or

[0616] CHCH₃;

[0617] Y=NR₁C(O)R₃;

[0618] NR₁C(O)R₅;

[0619] NR₁SO₂R₃;

[0620] NR₁C(O)NHR₃;or

[0621] NR₁C(O)OR₆

[0622] R₅=C₃-C₇-cycloalkyl;

[0623] R₆=C₁-C₄-straight chain alkyl;

[0624] C₃-C₄-branched chain alkyl;

[0625] C₂-C₄-alkenyl chain;

[0626] (CH₂)_(n)Ph; or

[0627] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0628] or a pharmaceutically acceptable salt thereof;

[0629] said process comprising:

[0630] reacting a first intermediate compound having the same formula asthe purine derivative compound except that Y=NHR₁, with R₃COC₁ or R₅COC₁or R₃SO₂C₁ or R₃NCO or R₆OC(O)Cl under conditions effective to form thepurine derivative compound.

[0631] Yet another aspect of the present invention is directed to aprocess for preparation of a purine derivative compound of the formula:

[0632] wherein:

[0633] R₁ are the same or different and independently selected from thegroup consisting of:

[0634] H;

[0635] C₁-C₆-straight chain alkyl;

[0636] C₂-C₆-straight alkenyl chain;

[0637] C₃-C₆-branched alkyl chain;

[0638] C₃-C₆-branched alkenyl chain;

[0639] C₃-C₇-cycloalkyl;

[0640] CH₂—(C₃-C₇-cycloalkyl);

[0641] CH₂CF₃;

[0642] CH₂CH₂CF₃; and

[0643] CH(CF₃)₂;

[0644] the combination of X, D, and Q are either:

[0645] D=Q=N and X=CH; or

[0646] D=X=N and Q=CH; or

[0647] Q=X=N and D=CH; or

[0648] Q=N and D=X=CH;

[0649] V=NH;

[0650] O;

[0651] S; or

[0652] CH₂;

[0653] R₂=phenyl;

[0654] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from the group consistingof R₁, OR, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl,Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH;

[0655] 1-naphthyl;

[0656] 2-naphthyl;

[0657] heterocycles selected from the group consisting of:

[0658] 2-pyridyl;

[0659] 3-pyridyl;

[0660] 4-pyridyl;

[0661] 2-pyrimidyl;

[0662] 4-pyrimidyl;

[0663] 5-pyrimidyl;

[0664] thiophene-2-yl;

[0665] thiophene-3-yl;

[0666] 2-furanyl;

[0667] 3-furanyl;

[0668] oxazol-2-yl;

[0669] oxazol-4-yl;

[0670] oxazol-5-yl;

[0671] thiazol-2-yl;

[0672] thiazol-4-yl;

[0673] thiazol-5-yl;

[0674] imidazol-2-yl;

[0675] imidazol-4-yl;

[0676] pyrazol-3-yl;

[0677] pyrazol-4-yl;

[0678] isoxazol-3-yl;

[0679] isoxazol-4-yl;

[0680] isoxazol-5-yl;

[0681] isothiazol-3-yl;

[0682] isothiazol-4-yl;

[0683] isothiazol-5-yl;

[0684] 1,3,4-thiadiazol-2-yl;

[0685] benzo[b]furan-2-yl;

[0686] benzo[b]thiophene-2-yl;

[0687] 2-pyrrolyl;

[0688] 3-pyrrolyl;

[0689] 1,3,5-triazin-2-yl;

[0690] pyrazin-2-yl;

[0691] pyridazin-3-yl;

[0692] pyridazin-4-yl;

[0693] 2-quinolinyl;

[0694] 3-quinolinyl;

[0695] 4-quinolinyl;

[0696] 1-isoquinolinyl;

[0697] 3-isoquinolinyl; and

[0698] 4-isoquinolinyl; or

[0699] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from the groupconsisting of Br, Cl, F, R₁, and C(O)CH₃;

[0700] R₃ are the same or different and independently selected from thegroup consisting of:

[0701] H;

[0702] C₁-C₄-straight chain alkyl;

[0703] C₃-C₄-branched chain alkyl;

[0704] C₂-C₄-alkenyl chain;

[0705] (CH₂)_(n)Ph; and

[0706] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0707] R₄=H;

[0708] C₁-C₄-straight chain alkyl; or

[0709] C₃-C₄-branched chain alkyl;

[0710] R₃ and R₄ can be linked together by a carbon chain to form withintervening atoms a 5-8-membered saturated or unsaturated ring;

[0711] n₁=0-3;

[0712] n=0-3;

[0713] A=CH₂;

[0714] (CH₂)₂;

[0715] (CH₂)₃;

[0716] OCH₂CH₂; or

[0717] CHCH₃;

[0718] Y=NHC(O)CH(R₆)NH₂;

[0719] R₅=C₃-C₇-cycloalkyl;

[0720] R₆=C₁-C₄-straight chain alkyl;

[0721] C₃-C₄-branched chain alkyl;

[0722] C₂-C₄-alkenyl chain;

[0723] (CH₂)_(n)Ph; or

[0724] (CH₂)_(n)-substituted phenyl, wherein the phenyl sub stituentsare as defined above in R₂;

[0725] or a pharmaceutically acceptable salt thereof;

[0726] said process comprising:

[0727] reacting a first intermediate compound having the same formula asthe purine derivative compound except that Y is NH₂, with a compound ofthe formula: PNHCH(R₆)CO₂H under conditions effective to form the purinederivative compound after a suitable deprotection strategy,

[0728] wherein

[0729] P=C(O)OtBu;

[0730] C(O)OCH₂Ph;

[0731] Fmoc

[0732] Benzyl; or

[0733] Alloc.

[0734] The compounds of the present invention, as described in FormulaI, show significantly improved growth inhibition of human transformedcell lines and/or cyclin/cdk inhibition relative to compounds of theprior art. These compounds have been demonstrated to be potent growthinhibitors in dozens of human transformed cell lines. Olomoucine, astructurally related purine derivative, is a poor human transformed cellgrowth inhibition agent with GI₅₀ values in the 20,000-100,000 nM rangeover 60-transformed cell lines. By contrast, the compounds of thepresent invention demonstrate GI₅₀ values over 60-transformed cell linesin the <10-25,000 nM range, preferably in the <10-100 nM range over60-transformed cell lines, and, most preferably, <10 nM across 60-humantransformed cell lines. This finding is unexpected from the prior art,which specifically teaches that compounds of the present invention wouldnot be potent human transformed cell line growth inhibitors.

[0735] The R₂ group in Formula I imparts unexpected and significantimprovement in growth inhibition in human transformed cell lines, whilesubstitution of various groups at R₃ and R₄ found in Formula I impartimportant features that contribute to cyclin/cdk inhibition and growthinhibition of human transformed cell lines. Specifically, thecombination of the R₂ group and the substitutions within R₃ and R₄result in compounds with superior biological activity. Compounds whichare cyclin/cdk inhibitors and/or human transformed cell line growthinhibitors have utility in treating human proliferative cellulardisorders.

DETAILED DESCRIPTION OF THE INVENTION

[0736] The compounds of the present invention are represented by thechemical structure found in Formula I.

[0737] wherein:

[0738] R₁ are the same or different and independently selected from thegroup consisting of:

[0739] C₁-C₆-straight chain alkyl;

[0740] C₂-C₆-straight alkenyl chain;

[0741] C₃-C₆-branched alkyl chain;

[0742] C₃-C₆-branched alkenyl chain;

[0743] C₃-C₇-cycloalkyl;

[0744] CH₂-(C₃-C₇-cycloalkyl);

[0745] CH₂CF₃;

[0746] CH₂CH₂CF₃; and

[0747] CH(CF₃)₂;

[0748] the combination of X, D, and Q are either:

[0749] D=Q=N, and X=CH; or

[0750] D=X=N, and Q=CH; or

[0751] Q=X=N, and D=CH; or

[0752] Q=N, and D=X=CH;

[0753] V=NH;

[0754] O;

[0755] S; or

[0756] CH₂;

[0757] R₂=phenyl;

[0758] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from the group consistingof R₁, OR, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl,Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH;

[0759] 1-naphthyl;

[0760] 2-naphthyl;

[0761] heterocycles selected from the group consisting of:

[0762] 2-pyridyl;

[0763] 3-pyridyl;

[0764] 4-pyridyl;

[0765] 2-pyrimidyl;

[0766] 4-pyrimidyl;

[0767] 5-pyrimidyl;

[0768] thiophene-2-yl;

[0769] thiophene-3-yl;

[0770] 2-furanyl;

[0771] 3-furanyl;

[0772] oxazol-2-yl;

[0773] oxazol-4-yl;

[0774] oxazol-5-yl;

[0775] thiazol-2-yl;

[0776] thiazol-4-yl;

[0777] thiazol-5-yl;

[0778] imidazol-2-yl;

[0779] imidazol-4-yl;

[0780] pyrazol-3-yl;

[0781] pyrazol-4-yl;

[0782] isoxazol-3-yl;

[0783] isoxazol-4-yl;

[0784] isoxazol-5-yl;

[0785] isothiazol-3-yl;

[0786] isothiazol-4-yl;

[0787] isothiazol-5-yl;

[0788] 1,3,4-thiadiazol-2-yl;

[0789] benzo[b]furan-2-yl;

[0790] benzo[b]thiophene-2-yl;

[0791] 2-pyrrolyl;

[0792] 3-pyrrolyl;

[0793] 1,3,5-triazin-2-yl;

[0794] pyrazin-2-yl;

[0795] pyridazin-3-yl;

[0796] pyridazin-4-yl;

[0797] 2-quinolinyl;

[0798] 3-quinolinyl;

[0799] 4-quinolinyl;

[0800] 1-isoquinolinyl;

[0801] 3-isoquinolinyl; and

[0802] 4-isoquinolinyl; or

[0803] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from the groupconsisting of Br, Cl, F, R₁, and C(O)CH₃;

[0804] R₃ are the same or different and independently selected from thegroup consisting of:

[0805] H;

[0806] C₁-C₄-straight chain alkyl;

[0807] C₃-C₄-branched chain alkyl;

[0808] C₂-C₄-alkenyl chain;

[0809] (CH₂)_(n)Ph; and

[0810] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0811] R₄=H;

[0812] C₁-C₄-straight chain alkyl; or

[0813] C₃-C₄-branched chain alkyl;

[0814] R₃ and R₄ can be linked together by a carbon chain to form withintervening atoms a 5-8-membered saturated or unsaturated ring;

[0815] n₁=0-3;

[0816] n=0-3;

[0817] A=CH₂;

[0818] (CH₂)₂;

[0819] (CH₂)₃;

[0820] OCH₂CH₂; or

[0821] CHCH₃;

[0822] Y=H;

[0823] OR₁;

[0824] N(R₁)₂;

[0825] N(R₁)C(O)R₃;

[0826] N(R₁)C(O)R₅;

[0827] N(R₁)C(O)CH(R₆)NH₂;

[0828] N(R₁)SO₂R₃;

[0829] N(R₁)C(O)NHR₃; or

[0830] N(R₁)C(O)OR₆;

[0831] R₅=C₃-C₇-cycloalkyl;

[0832] R₆=C₁-C₄-straight chain alkyl;

[0833] C₃-C₄-branched chain alkyl;

[0834] C₂-C₄-alkenyl chain;

[0835] (CH₂)_(n)Ph; or

[0836] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0837] or a pharmaceutically acceptable salt thereof.

[0838] More preferably, the compounds of the current invention arerepresented by the chemical structure found in Formula III.

[0839] wherein:

[0840] R₁ are the same or different and independently selected from thegroup consisting of: H;

[0841] C₁-C₆-straight chain alkyl;

[0842] C₂-C₆-straight alkenyl chain;

[0843] C₃-C₆-branched alkyl chain;

[0844] C₃-C₆-branched alkenyl chain;

[0845] C₃-C₇-cycloalkyl;

[0846] CH₂—(C₃-C₇-cycloalkyl);

[0847] CH₂CF₃;

[0848] CH₂CH₂CF₃; and

[0849] CH(CF₃)₂;

[0850] the combination of X, D, and Q are either:

[0851] D=Q=N, and X=CH; or

[0852] D=X=N, and Q=CH; or

[0853] Q=X=N, and D=CH; or

[0854] Q=N, and D=X=CH;

[0855] V=NH;

[0856] O;

[0857] S; or

[0858] CH₂;

[0859] R₂=phenyl;

[0860] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from the group consistingof R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl,Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, and C(O)NHCHR₁CH₂OH;

[0861] 1-naphthyl;

[0862] 2-naphthyl;

[0863] heterocycles selected from the group consisting of:

[0864] 2-pyridyl;

[0865] 3-pyridyl;

[0866] 4-pyridyl;

[0867] 2-pyrimidyl;

[0868] 4-pyrimidyl;

[0869] 5-pyrimidyl;

[0870] thiophene-2-yl;

[0871] thiophene-3-yl;

[0872] 2-furanyl;

[0873] 3-furanyl;

[0874] oxazol-2-yl;

[0875] oxazol-4-yl;

[0876] oxazol-5-yl;

[0877] thiazol-2-yl;

[0878] thiazol-4-yl;

[0879] thiazol-5-yl;

[0880] imidazol-2-yl;

[0881] imidazol-4-yl;

[0882] pyrazol-3-yl;

[0883] pyrazol-4-yl;

[0884] isoxazol-3-yl;

[0885] isoxazol-4-yl;

[0886] isoxazol-5-yl;

[0887] isothiazol-3-yl;

[0888] isothiazol-4-yl;

[0889] isothiazol-5-yl;

[0890] 1,3,4-thiadiazol-2-yl;

[0891] benzo[b]furan-2-yl;

[0892] benzo[b]thiophene-2-yl;

[0893] 2-pyrrolyl;

[0894] 3-pyrrolyl;

[0895] 1,3,5-triazin-2-yl;

[0896] pyrazin-2-yl;

[0897] pyridazin-3-yl;

[0898] pyridazin-4-yl;

[0899] 2-quinolinyl;

[0900] 3-quinolinyl;

[0901] 4-quinolinyl;

[0902] 1-isoquinolinyl;

[0903] 3-isoquinolinyl; and

[0904] 4-isoquinolinyl; or

[0905] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from the groupconsisting of Br, Cl, F, R₁, and C(O)CH₃;

[0906] n=0-3;

[0907] A=CH₂;

[0908] (CH₂)₂;

[0909] (CH₂)₃;

[0910] OCH₂CH₂; or

[0911] CHCH₃;

[0912] Y=H;

[0913] OR₁;

[0914] N(R₁)₂;

[0915] N(R₁)C(O)R₃;

[0916] N(R₁)C(O)R₅;

[0917] N(R₁)C(O)CH(R₆)NH₂;

[0918] N(R₁)SO₂R₃;

[0919] N(R₁)C(O)NHR₃; or

[0920] N(R₁)C(O)OR₆;

[0921] R₃ are the same or different and independently selected from thegroup consisting of:

[0922] H;

[0923] C₁-C₄-straight chain alkyl;

[0924] C₃-C₄-branched chain alkyl;

[0925] C₂-C₄-alkenyl chain;

[0926] (CH₂)_(n)Ph; and

[0927] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[0928] R₅=C₃-C₇-cycloalkyl;

[0929] R₆=C₁-C₄-straight chain alkyl;

[0930] C₃-C₄-branched chain alkyl; or

[0931] C₂-C₄-alkenyl chain;

[0932] or a pharmaceutically acceptable salt thereof.

[0933] In another embodiment, the present invention is directed to amethod of treating a mammal with a disorder mediated by elevated levelsof cellular proliferation comprising administering a therapeuticallyeffective amount of the compound of the present invention to the mammalunder conditions effective to treat the disorder mediated by elevatedlevels of cell proliferation.

[0934] The compounds of the present invention can be administeredorally, parenterally, for example, subcutaneously, intravenously,intramuscularly, intraperitoneally, by intranasal instillation, or byapplication to mucous membranes, such as, that of the nose, throat, andbronchial tubes. They may be administered alone or with suitablepharmaceutical carriers, and can be in solid or liquid form such as,tablets, capsules, powders, solutions, suspensions, or emulsions.

[0935] Based on the results obtained in the standard pharmacologicaltest procedures described below, the compounds of the present inventionare useful as antineoplastic agents. More particularly, the compounds ofthe present invention are useful for inhibiting the growth of neoplasticcells, causing cell death of neoplastic cells, and eradicatingneoplastic cells. The compounds of the present invention are, therefore,useful for treating solid tumors, including sarcomas and carcinomas,such as astrocytomas, prostate cancer, breast cancer, small cell lungcancer, and ovarian cancer, leukemias, lymphomas, adult T-cellleukemia/lymphoma, and other neoplastic disease states.

[0936] In addition to the utilities described above, many of thecompounds of the present invention are useful in the preparation ofother compounds.

[0937] The active compounds of the present invention may be orallyadministered, for example, with an inert diluent, or with an assimilableedible carrier, or they may be enclosed in hard or soft shell capsules,or they may be compressed into tablets, or they may be incorporateddirectly with the food of the diet. For oral therapeutic administration,these active compounds may be incorporated with excipients and used inthe form of tablets, capsules, elixirs, suspensions, syrups, and thelike. Such compositions and preparations should contain at least 0.1% ofactive compound. The percentage of the compound in these compositionsmay, of course, be varied and may conveniently be between about 2% toabout 60% of the weight of the unit. The amount of active compound insuch therapeutically useful compositions is such that a suitable dosagewill be obtained. Preferred compositions according to the presentinvention are prepared so that an oral dosage unit contains betweenabout 1 and 250 mg of active compound.

[0938] The tablets, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch, or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose, or saccharin. When thedosage unit form is a capsule, it may contain, in addition to materialsof the above type, a liquid carrier such as a fatty oil.

[0939] Various other materials may be present as coatings or to modifythe physical form of the dosage unit. For instance, tablets may becoated with shellac, sugar, or both. A syrup may contain, in addition toactive ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye, and flavoring such as cherry ororange flavor.

[0940] These active compounds may also be administered parenterally.Solutions or suspensions of these active compounds can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Illustrative oils are those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, or mineral oil. In general, water, saline, aqueousdextrose and related sugar solution, and glycols such as, propyleneglycol or polyethylene glycol, are preferred liquid carriers,particularly for injectable solutions. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

[0941] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms, such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0942] The compounds of the present invention may also be administereddirectly to the airways in the form of an aerosol. For use as aerosols,the compounds of the present invention in solution or suspension may bepackaged in a pressurized aerosol container together with suitablepropellants, for example, hydrocarbon propellants like propane, butane,or isobutane with conventional adjuvants. The materials of the presentinvention also may be administered in a non-pressurized form such as ina nebulizer or atomizer.

[0943] General Synthetic Schemes

[0944] The compounds of the present invention can be prepared byconventional methods of organic synthesis practiced by those skilled inthe art. The general reaction sequences outlined below are generalmethods useful for preparing the compounds of the present invention andare not meant to be limiting in scope or utility.

[0945] Reaction of 2,6-dichloropurine (Formula IV) with various aminesof Formula V, many of which are commercially available or prepared byliterature methods or modifications of literature methods, in thepresence of a polar solvent, such as ethanol, provides purines ofFormula VI (General Flowsheet I, infra). Reaction of purines of FormulaVI with alkyl halides (R₁-Z) in the presence of a base such as potassiumcarbonate provides N1-alkylated purines of Formula VII. Chloridedisplacement of N1-alkylated purines of Formula VII with amines, thiolsor alcohols of structure Formula VIII, either in neat solution or in aninert solvent such as ethanol or butanol, with or without a base such assodium hydride as appropriate, at an appropriate temperature providespurines of Formula IX (V═NH, O, S). Transition metal-mediatedcross-coupling reaction of purines of Formula IX with boronic acid(R₂—B(OH)₂) or tin reagents (R₂—Sn(n-Bu)₃ or R₂—SnMe₃) provides purinesof Formula X (V═NH, O, S). If in Formula X (Y═NH₂), then subsequentreaction of Formula X (Y═NH₂) with acid chloride (R₃COCl), or sulfonylchloride (R₃SO₂Cl), or isocyanate (R₃NCO), or chloroformate (ClC(O)OR₆)reagents provides purines of Formula XI wherein Y═NHC(O)R₃, NHSO₂R₃, orNHC(O)NHR₃, or NHC(O)OR₆, respectively. On the other hand, if in FormulaX, Y already is OR₁ or NHC(O)R₃ or NHSO₂R₃ or NHC(O)NHR₃ or NHC(O)OR₆,as a result of what Y started out as in Formula VIII, then this laststep is unnecessary.

[0946] Reaction of purines of Formula VII, with alkenyl tin reagents ofFormula XII, which are prepared by conventional methods described in theliterature, in the presence of a transition metal catalyst, such asPd(0), provides purines of Formula XIII (General Flowsheet II, infra).Subsequent reaction of purines of Formula XIII with boronic acid(R₂-B(OH)₂) or tin reagents (R₂—Sn(n-Bu)₃ or R₂—SnMe₃) in the presenceof a transition metal catalyst, such as Pd(0), provides purines ofFormula XV. Alternatively, by switching the order of reactions dependenton the precise reactivity of the purine of Formula VII, reaction ofpurines of Formula VII with boronic acid (R₂—B(OH)₂) or tin reagents(R₂—Sn(n-Bu)₃ or R₂—SnMe₃) in the presence of a transition metalcatalyst, such as Pd(0), provides purines of Formula XIV. Subsequentreaction of purines of Formula XIV, with alkenyl tin reagents of FormulaXII, which are prepared by conventional methods described in theliterature, in the presence of a transition metal catalyst, such asPd(0), provides purines of Formula XV. Finally reduction of the olefinwithin Formula XV provides purines of Formula X (V=CH₂).

[0947] Definitions of the groups include:

[0948] Z=Br;

[0949] I;

[0950] V=NH₂;

[0951] OH;

[0952] SH;

[0953] R₁ are the same or different and independently selected from:

[0954] H;

[0955] C₁-C₆-straight chain alkyl;

[0956] C₂-C₆-straight alkenyl chain;

[0957] C₃-C₆-branched alkyl chain;

[0958] C₃-C₆-branched alkenyl chain;

[0959] C₃-C₇-cycloalkyl;

[0960] CH₂—(C₃-C₇-cycloalkyl);

[0961] CH₂CF₃;

[0962] CH₂CH₂CF₃;

[0963] CH(CF₃)₂;

[0964] the combination of X, D, and Q are selected from:

[0965] D=Q=N, and X=CH;

[0966] D=X=N, and Q=CH;

[0967] Q=X=N, and D=CH;

[0968] Q=N, and D=X=CH;

[0969] V=NH;

[0970] O;

[0971] S;

[0972] CH₂;

[0973] R₂ can be in any position on the ring and selected from:

[0974] phenyl;

[0975] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from R₁, OR₁, SR₁,S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁,C(O)NHR₁, phenyl, C(O)NHCHR₁CH₂OH;

[0976] 1-naphthyl;

[0977] 2-naphthyl;

[0978] heterocycles including:

[0979] 2-pyridyl;

[0980] 3-pyridyl;

[0981] 4-pyridyl;

[0982] 2-pyrimidyl;

[0983] 4-pyrimidyl;

[0984] 5-pyrimidyl;

[0985] thiophene-2-yl;

[0986] thiophene-3-yl;

[0987] 2-furanyl;

[0988] 3-furanyl;

[0989] oxazol-2-yl;

[0990] oxazol-4-yl;

[0991] oxazol-5-yl;

[0992] thiazol-2-yl;

[0993] thiazol-4-yl;

[0994] thiazol-5-yl;

[0995] imidazol-2-yl;

[0996] imidazol-4-yl;

[0997] pyrazol-3-yl;

[0998] pyrazol-4-yl;

[0999] isoxazol-3-yl;

[1000] isoxazol-4-yl;

[1001] isoxazol-5-yl;

[1002] isothiazol-3-yl;

[1003] isothiazol-4-yl;

[1004] isothiazol-5-yl;

[1005] 1,3,4-thiadiazol-2-yl;

[1006] benzo[b]furan-2-yl;

[1007] benzo[b]thiophene-2-yl;

[1008] 2-pyrrolyl;

[1009] 3-pyrrolyl;

[1010] 1,3,5-triazin-2-yl;

[1011] pyrazin-2-yl;

[1012] pyridazin-3-yl;

[1013] pyridazin-4-yl;

[1014] 2-quinolinyl;

[1015] 3-quinolinyl;

[1016] 4-quinolinyl;

[1017] 1-isoquinolinyl;

[1018] 3-isoquinolinyl;

[1019] 4-isoquinolinyl;

[1020] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from Br, Cl, F, R₁,C(O)CH₃;

[1021] R₃ are the same or different and independently selected from:

[1022] H;

[1023] C₁-C₄-straight chain alkyl;

[1024] C₃-C₄-branched chain alkyl;

[1025] C₂-C₄-alkenyl chain;

[1026] (CH₂)_(n)Ph;

[1027] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[1028] R₄=H

[1029] C₁-C₄-straight chain alkyl;

[1030] C₃-C₄-branched chain alkyl;

[1031] R₃ and R₄ can be linked together by a carbon chain to form a5-8-membered saturated or unsaturated ring;

[1032] n₁=0-3;

[1033] n=0-3;

[1034] A=(CH₂);

[1035] (CH₂)₂;

[1036] (CH₂)₃;

[1037] (OCH₂CH₂);

[1038] (CHCH₃);

[1039] Y=H;

[1040] OR₁;

[1041] N(R₁)₂;

[1042] N(R₁)C(O)R₃;

[1043] N(R₁)C(O)R₅;

[1044] N(R₁)C(O)CH(R₆)NH₂;

[1045] N(R₁)SO₂R₃;

[1046] N(R₁)C(O)NHR₃;

[1047] N(R₁)C(O)OR₆;

[1048] R₅=C₃-C₇-cycloalkyl;

[1049] R₆=C₁-C₄-straight chain alkyl;

[1050] C₃-C₄-branched chain alkyl;

[1051] C₂-C₄-alkenyl chain;

[1052] (CH₂)_(n)Ph;

[1053] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂.

[1054] Additional, general non-limiting syntheses of compounds of thepresent invention of Formula X and Formula XI are shown below in GeneralFlowsheet III.

[1055] Reaction of various amines of Formula V, many of which arecommercially available or prepared by literature methods ormodifications of literature methods, with boronic acid (R₂—B(OH)₂) ortin reagents (R₂—Sn(n-Bu)₃) or (R₂—SnMe₃) in the presence of atransition metal catalyst, such as Pd(0), provides biaryl amines ofFormula XVII. Reaction of 2,6-dichloropurine (Formula IV) with variousamines of Formula XVII, in the presence of a polar solvent, such asethanol, provides purines of Formula XVIII. Reaction of purines ofFormula XVIII with alkyl halides (R₁-Z) in the presence of a base suchas potassium carbonate provides N1-alkylated purines of Formula XIV.Chloride displacement of NI-alkylated purines of Formula XIV withamines, thiols or alcohols of Formula VIII, either in neat solution orin an inert solvent such as ethanol or butanol, with or without a basesuch as sodium hydride as appropriate, at an appropriate temperatureprovides purines of Formula X (V═NH, O, S). If in Formula X (Y═NH₂),then subsequent reaction of Formula X (Y═NH₂) with acid chloride(R₃COCl), or sulfonyl chloride (R₃SO₂Cl), or isocyanate (R₃NCO), orchloroformate (ClC(O)OR₆) reagents provides purines of Formula XIwherein Y═NHC(O)R₃, NHSO₂R₃, or NHC(O)NHR₃, or NHC(O)OR₆, respectively.On the other hand, if in Formula X, Y already is OR₁ or NHC(O)R₃ orNHSO₂R₃ or NHC(O)NHR₃ or NHC(O)OR₆, as a result of what Y started out asin Formula VIII, then this last step is unnecessary.

[1056] Definitions of the groups include:

[1057] Z=Br;

[1058] V₁=NH₂;

[1059] OH;

[1060] SH;

[1061] R₁ are the same or different and independently selected from:

[1062] H;

[1063] C₁-C₆-straight chain alkyl;

[1064] C₂-C₆-straight alkenyl chain;

[1065] C₃-C₆-branched alkyl chain;

[1066] C₃-C₆-branched alkenyl chain;

[1067] C₃-C₇-cycloalkyl;

[1068] CH₂—(C₃-C₇-cycloalkyl);

[1069] CH₂CF₃;

[1070] CH₂CH₂CF₃;

[1071] CH(CF₃)₂;

[1072] the combination of X, D, and Q are selected from:

[1073] D=Q=N, and X=CH;

[1074] D=X=N, and Q=CH;

[1075] Q=X=N, and D=CH;

[1076] Q=N, and D=X=CH;

[1077] V=NH;

[1078] O;

[1079] S;

[1080] CH₂;

[1081] R₂ can be in any position on the ring and selected from:

[1082] phenyl;

[1083] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from R₁, OR₁, SR₁,S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁,C(O)NHR₁, phenyl, C(O)NHCHR₁CH₂OH;

[1084] 1-naphthyl;

[1085] 2-naphthyl;

[1086] heterocycles including:

[1087] 2-pyridyl;

[1088] 3-pyridyl;

[1089] 4-pyridyl;

[1090] 2-pyrimidyl;

[1091] 4-pyrimidyl;

[1092] 5-pyrimidyl;

[1093] thiophene-2-yl;

[1094] thiophene-3-yl;

[1095] 2-furanyl;

[1096] 3-furanyl;

[1097] oxazol-2-yl;

[1098] oxazol-4-yl;

[1099] oxazol-5-yl;

[1100] thiazol-2-yl;

[1101] thiazol-4-yl;

[1102] thiazol-5-yl;

[1103] imidazol-2-yl;

[1104] imidazol-4-yl;

[1105] pyrazol-3-yl;

[1106] pyrazol-4-yl;

[1107] isoxazol-3-yl;

[1108] isoxazol-4-yl;

[1109] isoxazol-5-yl;

[1110] isothiazol-3-yl;

[1111] isothiazol-4-yl;

[1112] isothiazol-5-yl;

[1113] 1,3,4-thiadiazol-2-yl;

[1114] benzo[b]furan-2-yl;

[1115] benzo[b]thiophene-2-yl;

[1116] 2-pyrrolyl;

[1117] 3-pyrrolyl;

[1118] 1,3,5-triazin-2-yl;

[1119] pyrazin-2-yl;

[1120] pyridazin-3-yl;

[1121] pyridazin-4-yl;

[1122] 2-quinolinyl;

[1123] 3-quinolinyl;

[1124] 4-quinolinyl;

[1125] 1-isoquinolinyl;

[1126] 3-isoquinolinyl;

[1127] 4-isoquinolinyl;

[1128] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from Br, Cl, F, R₁,C(O)CH₃;

[1129] R₃ are the same or different and independently selected from:

[1130] H;

[1131] C₁-C₄-straight chain alkyl;

[1132] C₃-C₄-branched chain alkyl;

[1133] C₂-C₄-alkenyl chain;

[1134] (CH₂)_(n)Ph;

[1135] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[1136] R₄=H;

[1137] C₁-C₄-straight chain alkyl;

[1138] C₃-C₄-branched chain alkyl;

[1139] R₃ and R₄ can be linked together by a carbon chain to form a5-8-membered saturated or unsaturated ring;

[1140] n₁=0-3;

[1141] n=0-3;

[1142] A=(CH₂);

[1143] (CH₂)₂;

[1144] (CH₂)₃;

[1145] (OCH₂CH₂);

[1146] (CHCH₃);

[1147] Y=H;

[1148] OR₁;

[1149] N(R₁)₂;

[1150] N(R₁)C(O)R₃;

[1151] N(R₁)C(O)R₅;

[1152] N(R₁)C(O)CH(R₆)NH₂;

[1153] N(R₁)SO₂R₃;

[1154] N(R₁)C(O)NHR₃;

[1155] N(R₁)C(O)OR₆;

[1156] R₅=C₃-C₇-cycloalkyl;

[1157] R₆=C₁-C₄-straight chain alkyl;

[1158] C₃-C₄-branched chain alkyl;

[1159] C₂-C₄-alkenyl chain;

[1160] (CH₂)_(n)Ph;

[1161] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂.

[1162] Additional, general non-limiting syntheses of compounds of thepresent invention of Formula XVI, Formula XVII and Formula XVIII areshown below in General Flowsheet IV.

[1163] If in Formula X (Y═NH₂), then subsequent reaction of Formula X(Y═NH₂) with alkyl halide (R₈CH₂Z), an appropriate base, and a solvent;or reaction of Formula X (Y═NH₂) with aldehyde (R₈CHO) in the presenceof a solvent and a suitable reducing agent provides purines of FormulaXVI wherein Y═NHR₁, or N(R₁)₂. On the other hand, if in Formula X, Yalready is NHR₁, or N(R₁)₂, as a result of what Y started out as inFormula X, then this last step is unnecessary. If in Formula XVI(Y═NHR₁), then subsequent reaction of Formula XVI (Y═NHR₁) with acidchloride (R₃COCl), or sulfonyl chloride (R₃SO₂Cl), or isocyanate(R₃NCO), or chloroformate (ClC(O)OR₆) reagents provides purines ofFormula XX wherein Y═NR₁C(O)R₃, or NR₁C(O)R₅, or NR₁SO₂R₃, orNR₁C(O)NHR₃, or NR₁C(O)OR₆, respectively. On the other hand, if inFormula XVI, Y already is NR₁C(O)R₃, or NR₁C(O)R₅, or NR₁SO₂R₃, orNR₁C(O)NHR₃, or NR₁C(O)OR₆, as a result of what started out as inFormula XVI, then this last step is unnecessary.

[1164] If in Formula X (Y═NH₂), then subsequent reaction of Formula X(Y═NH₂) with acid (PNHCH(R₆)CO₂H), in a suitable solvent in the presenceof an appropriate coupling agent provides a purine derivative; whichupon suitable deprotection provides purines of Formula XIX whereinY═NHC(O)CH(R₆)NH₂. On the other hand, if in Formula X, Y already isNHC(O)CH(R₆)NH₂, as a result of what Y started out as in Formula X, thenthis last step is unnecessary.

[1165] Definitions of the groups include:

[1166] Z=Br;

[1167] P=C(O)OtBu;

[1168] C(O)OCH₂Ph;

[1169] Fmoc;

[1170] Benzyl;

[1171] Alloc;

[1172] R₁ are the same or different and independently selected from:

[1173] H;

[1174] C₁-C₆-straight chain alkyl;

[1175] C₂-C₆-straight alkenyl chain;

[1176] C₃-C₆-branched alkyl chain;

[1177] C₃-C₆-branched alkenyl chain;

[1178] C₃-C₇-cycloalkyl;

[1179] CH₂—(C₃-C₇-cycloalkyl);

[1180] CH₂CF₃;

[1181] CH₂CH₂CF₃;

[1182] CH(CF₃)₂;

[1183] the combination of X, D, and Q are selected from:

[1184] D=Q=N, and X=CH;

[1185] D=X=N, and Q=CH;

[1186] Q=X=N, and D=CH;

[1187] Q=N, and D=X=CH;

[1188] V=NH;

[1189] O;

[1190] S;

[1191] CH₂;

[1192] R₂ can be in any position on the ring and selected from:

[1193] phenyl;

[1194] substituted phenyl, wherein the substituents (1-2 in number) arein any position and are independently selected from R₁, OR₁, SR₁,S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃, NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁,C(O)NHR₁, phenyl, C(O)NHCHR₁CH₂OH;

[1195] 1-naphthyl;

[1196] 2-naphthyl;

[1197] heterocycles including:

[1198] 2-pyridyl;

[1199] 3-pyridyl;

[1200] 4-pyridyl;

[1201] 2-pyrimidyl;

[1202] 4-pyrimidyl;

[1203] 5-pyrimidyl;

[1204] thiophene-2-yl;

[1205] thiophene-3-yl;

[1206] 2-furanyl;

[1207] 3-furanyl;

[1208] oxazol-2-yl;

[1209] oxazol-4-yl;

[1210] oxazol-5-yl;

[1211] thiazol-2-yl;

[1212] thiazol-4-yl;

[1213] thiazol-5-yl;

[1214] imidazol-2-yl;

[1215] imidazol-4-yl;

[1216] pyrazol-3-yl;

[1217] pyrazol-4-yl;

[1218] isoxazol-3-yl;

[1219] isoxazol-4-yl;

[1220] isoxazol-5-yl;

[1221] isothiazol-3-yl;

[1222] isothiazol-4-yl;

[1223] isothiazol-5-yl;

[1224] 1,3,4-thiadiazol-2-yl;

[1225] benzo[b]furan-2-yl;

[1226] benzo[b]thiophene-2-yl;

[1227] 2-pyrrolyl;

[1228] 3-pyrrolyl;

[1229] 1,3,5-triazin-2-yl;

[1230] pyrazin-2-yl;

[1231] pyridazin-3-yl;

[1232] pyridazin-4-yl;

[1233] 2-quinolinyl;

[1234] 3-quinolinyl;

[1235] 4-quinolinyl;

[1236] 1-isoquinolinyl;

[1237] 3-isoquinolinyl;

[1238] 4-isoquinolinyl;

[1239] substituted heterocycle, wherein the substituents (1-2 in number)are in any position and are independently selected from Br, Cl, F, R₁,C(O)CH₃;

[1240] R₃ are the same or different and independently selected from:

[1241] H;

[1242] C₁-C₄-straight chain alkyl;

[1243] C₃-C₄-branched chain alkyl;

[1244] C₂-C₄-alkenyl chain;

[1245] (CH₂)_(n)Ph;

[1246] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[1247] R₄=H;

[1248] C₁-C₄-straight chain alkyl;

[1249] C₃-C₄-branched chain alkyl;

[1250] R₃ and R₄ can be linked together by a carbon chain to form a5-8-membered saturated or unsaturated ring;

[1251] n₁=0-3;

[1252] n=0-3;

[1253] A=(CH₂);

[1254] (CH₂)₂;

[1255] (CH₂)₃;

[1256] (OCH₂CH₂);

[1257] (CHCH₃);

[1258] Y=H;

[1259] OR₁;

[1260] N(R₁)₂;

[1261] N(R₁)C(O)R₃;

[1262] N(R₁)C(O)R₅;

[1263] N(R₁)C(O)CH(R₆)NH₂;

[1264] N(R₁)SO₂R₃;

[1265] N(R₁)C(O)NHR₃;

[1266] N(R₁)C(O)OR₆;

[1267] R₅=C₃-C₇-cycloalkyl;

[1268] R₆=C₁-C₄-straight chain alkyl;

[1269] C₃-C₄-branched chain alkyl;

[1270] C₂-C₄-alkenyl chain;

[1271] (CH₂)_(n)Ph;

[1272] (CH₂)_(n)-substituted phenyl, wherein the phenyl substituents areas defined above in R₂;

[1273] R₈=C₁-C₅-straight chain alkyl;

[1274] C₂-C₅-straight alkenyl chain;

[1275] C₃-C₅-branched alkyl chain;

[1276] C₃-C₅-branched alkenyl chain;

[1277] C₃-C₇-cycloalkyl;

[1278] CF₃;

[1279] CH₂CF₃.

[1280] The synthesis of compound 5 is shown below in Scheme I.

[1281] The synthesis of compound 11 is shown below in Scheme II.

[1282] The syntheses of compounds 12, 13 and 14 are shown below inScheme III.

[1283] The synthesis of compound 17 is shown below in Scheme IV.

[1284] The synthesis of compound 17 is shown below in Scheme V.

[1285] The synthesis of compound 25 is shown below in Scheme VI.

[1286] An alternative synthesis of compound 25 is shown below in SchemeVII.

[1287] The synthesis of compound 32 is shown below in Scheme VIII.

[1288] The syntheses of compounds 33 and 34 are shown below in SchemeIX.

[1289] The syntheses of compounds 36, 38, and 40 are shown below inScheme X.

[1290] The synthesis of compound 43 is shown below in Scheme XI.

[1291] The synthesis of compound 46 is shown below in Scheme XII.

[1292] The synthesis of compound 48 and 50 are shown below in SchemeXIII.

[1293] The synthesis of compound 53 is shown below in Scheme XIV.

[1294] The synthesis of compound 54 is shown below in Scheme XV.

[1295] The synthesis of compound 56 is shown below in Scheme XVI.

[1296] The synthesis of compound 58 is shown below in Scheme XVII.

[1297] The synthesis of compound 60 is shown below in Scheme XVIII.

[1298] The syntheses of compounds 61, and 62 are shown below in SchemeXIX.

[1299] The syntheses of compounds 64, and 65 are shown below in SchemeXX.

[1300] The syntheses of compounds 66, and 67 are shown below in SchemeXXI.

[1301] The synthesis of compound 73 is shown below in Scheme XXII.

[1302] The syntheses of compounds 74, 75, and 76 are shown below inScheme XXIII.

[1303] The synthesis of compound 77 is shown below in Scheme XXIV.

[1304] The synthesis of compound 78 is shown below in Scheme XXV.

[1305] An alternative synthesis of compound 78, and the synthesis ofcompound 79 are shown below in Scheme XXVI.

[1306] The synthesis of compound 80 is shown below in Scheme XXVII.

[1307] The syntheses of compounds 86, and 87 are shown below in SchemeXXVIII.

[1308] The syntheses of compound 88 is shown below in Scheme XXIX.

[1309] The syntheses of compounds 93, and 94 are shown below in SchemeXXX.

[1310] The syntheses of compounds 95, and 96 are shown below in SchemeXXXI.

[1311] The syntheses of compound 97 is shown below in Scheme XXXII.

[1312] The syntheses of compounds 98, and 99 are shown below in SchemeXXXIII.

[1313] The syntheses of compound 100 is shown below in Scheme XXXIV.

[1314] The syntheses of compounds 101, and 102 are shown below in SchemeXXXV.

[1315] The syntheses of compounds 103, and 104 are shown below in SchemeXXXVI.

[1316] The syntheses of compounds 106, 107, and 108 are shown below inScheme XXXVII.

[1317] The syntheses of compounds 109, and 110 are shown below in SchemeXXXVIII.

[1318] The syntheses of compounds 111, and 112 are shown below in SchemeXXXIX.

[1319] The synthesis of compound 113 is shown below in Scheme XL.

[1320] The syntheses of compounds 114, 115, 116, and 117 are shown belowin Scheme

[1321] The syntheses of compound 118 is shown below in Scheme XLII.

[1322] The syntheses of compounds 123 and 124 are shown below in SchemeXLIII.

[1323] The syntheses of compounds 131 and 132 are shown below in SchemeXLIV.

[1324] The syntheses of compounds 134 and 135 are shown below in SchemeXLV.

[1325] The synthesis of compound 137 is shown below in Scheme XLVI.

[1326] The syntheses of compounds 139 and 140 are shown below in SchemeXLVII.

[1327] The synthesis of compound 142 is shown below in Scheme XLVIII.

[1328] The synthesis of compound 144 is shown below in Scheme XLIX.

[1329] The synthesis of compound 146 is shown below in Scheme L.

[1330] The synthesis of compound 148 is shown below in Scheme LI.

[1331] The syntheses of compounds 149-152 are shown below in Scheme LII.

[1332] The syntheses of compounds 153-156 are shown below in SchemeLIII.

[1333] The syntheses of compounds 157-159 are shown below in Scheme LIV.

[1334] The syntheses of compounds 160-163 are shown below in Scheme LV.

[1335] The syntheses of compounds 164-166 are shown below in Scheme LVI.

[1336] The syntheses of compounds 167-168 are shown below in SchemeLVII.

[1337] The syntheses of compounds 169-171 are shown below in SchemeLVIII.

[1338] The syntheses of compounds 172-173 are shown below in Scheme LIX.

[1339] The syntheses of compounds 174-176 are shown below in Scheme LX.

[1340] The syntheses of compounds 177-178 are shown below in Scheme LXI.

[1341] The syntheses of compounds 179-180 are shown below in SchemeLXII.

[1342] The syntheses of compounds 181-182 are shown below in SchemeLXIII.

[1343] The syntheses of compounds 187-188 are shown below in SchemeLXIV.

[1344] The syntheses of compounds 193 and 194 are shown below in SchemeLXV.

[1345] The syntheses of compounds 199-200 are shown below in SchemeLXVI.

[1346] The syntheses of compounds 205-206 are shown below in SchemeLXVII.

[1347] The syntheses of compounds 207-210 are shown below in SchemeLXVIII.

[1348] The syntheses of compounds 211-212 are shown below in SchemeLXIX.

[1349] The syntheses of compounds 213-215 are shown below in Scheme LXX.

[1350] The syntheses of compounds 216-217 are shown below in SchemeLXXI.

[1351] The syntheses of compounds 218-219 are shown below in SchemeLXXII.

[1352] The synthesis of compounds 221 is shown below in Scheme LXXIII.

[1353] The synthesis of compound 222 is shown below in Scheme LXXIV.

[1354] The synthesis of compound 223 is shown below in Scheme LXXV.

[1355] The synthesis of compound 224 is shown below in Scheme LXXVI.

[1356] The synthesis of compound 229 is shown below in Scheme LXXVII.

[1357] The syntheses of compounds 230-233 are shown below in SchemeLXXVIII.

[1358] The syntheses of compounds 239-241 are shown below in SchemeLXXIX.

[1359] The syntheses of compounds 242-243 are shown below in SchemeLXXX.

[1360] The syntheses of compounds 248-250 are shown below in SchemeLXXX.

[1361] The syntheses of compounds 123 and 124 are shown below in SchemeLXXXII.

[1362] The syntheses of compounds 258-260 are shown below in SchemeLXXXIII.

[1363] The syntheses of compounds 261-263 are shown below in SchemeLXXXIV.

[1364] The syntheses of compounds 264-265 are shown below in SchemeLXXXV.

[1365] The synthesis of compound 266 is shown below in Scheme LXXXVI.

EXAMPLES

[1366] Proton NMR spectra were obtained on a Bruker AC 300 spectrometerat 300 MHz or a Bruker 500 MHz spectrometer and were referenced totetramethylsilane as an internal standard. The IR spectrometer used wasa single beam Perkin-Elmer Spectrum 1000 FT-IR. All IR spectra obtainedwere prepared in a pressed disc of KBr. All IR spectra obtained wereacquired with a total of 4 accumulations at a resolution of 4.00 cm⁻¹.Melting points were obtained on a MeI-Temp II apparatus and areuncorrected. Mass spectra were obtained on either a Shimadzu QP-5000 ora PE Sciex API 150 Mass Spectrometer.

Example 1 Preparation of Compound 2

[1367] To the starting material 1 (1.0 g, 5.29 mmol) was added4-bromobenzylamine (2.53 g, 11.4 mmol), and EtOH (11 mL). The mixturewas stirred and heated at 50° C. in a round-bottomed flask and then H₂O(1 mL) and EtOH (10 mL) were added to dissolve the solids. The mixturewas refluxed for 1 h. Hünig's base (3.68 mL, 21.2 mmol) was added andrefluxed overnight, during which time a precipitate formed. The solutionwas filtered to provide a light yellow solid. The solid was dried invacuo (1.08 g, 60%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (bs, 1H), 8.15 (s,1H), 7.52 (d, 2H), 7.30 (d, 2H), 4.63 (bs, 2H); CI MS m/z=340[C₁₂H₉BrClN₅+H]⁺.

Example 2 Preparation of Compound 3

[1368] To the starting material 2 (1.08 g, 3.19 mmol) was added DMSO (11mL), K₂CO₃ (2.20 g, 15.95 mmol), and 2-iodopropane (1 mL, 9.57 mmol).The solution was stirred overnight then poured into H₂O (75 mL) andstirred. Additional H₂O (25-50 mL) was added to the mixture to form ayellow solid. The stirring was continued at 0° C. The solid was filteredin vacuo. The crude product was purified by silica gel chromatography toprovide 3 (0.66 g, 50%) as a white solid: mp 136-140° C.; ¹H NMR (300MHz, CDCl₃) δ 7.78 (s, 1H), 7.49 (d, 2H), 7.28 (d, 2H), 6.12 (bs, 1H),4.90-4.70 (m, 3H), 1.61 (d, 6H).

Example 3 Preparation of Compound 4

[1369] To starting material 3 (1.44 g, 3.78 mmol) was added2-amino-1-butanol (5.06 g, 56.7 mmol) and ethanol (5 mL) and the mixturewas heated in a sealed tube in an oil bath at 150-160° C. for 48 h. Thecooled solution was transferred to a round-bottomed flask and theethanol was removed in vacuo. The crude product was purified by flashcolumn chromatography on silica gel to give 4 (0.90 g, 55%):

[1370]¹H NMR (300 MHz, CDCl₃) δ 7.44-7.41 (m, 3H), 7.23 (d, 2H), 6.22(s, 1H), 5.06 (s, 1H), 4.90 (d, 1H), 4.78-4.68 (m, 2H), 4.65-4.55 (m,1H), 3.91-3.80 (m, 2H), 3.66-3.60 (m, 1H), 1.66-1.47 (m, 8H), 1.04-0.99(t, 3H).

Example 4 Preparation of Compound 5

[1371] To starting material 4 (0.13 g, 0.29 mmol) was added3-acetamidophenylboronic acid (0.21 g, 1.19 mmol) and Pd(PPh₃)₄ (0.08 g,0.07 mmol), Na₂CO₃ (2M, 0.60 mL), and toluene (5 mL). The solution wasdegassed with argon for 10 min then heated at 130° C. for 6 h. Thecooled solution was diluted with water and then extracted with CH₂Cl₂(3×50 mL). The combined organic phases were washed with brine, driedover anhydrous Na₂SO₄, filtered, and concentrated to yield a viscousorange oil. The oil was purified by flash column chromatography onsilica gel and then the product crystallized upon standing to give 5(0.06 g, 41%) as a pale yellow solid: ¹H NMR (300 MHz, CDCl₃) δ8.01-7.21 (m, 9H), 6.48 (s, 1H), 4.97 (d, 1H), 4.82-4.70 (m, 2H),4.65-4.53 (m, 1H), 3.98-3.25 (m, 2H), 3.20-3.05 (m, 1H), 2.20 (s, 3H),1.69-1.45 (m, 8H), 1.07-0.98 (t, 3H).

Example 5 Preparation of Compound 7

[1372] To 4-iodobenzoic acid (52.2 g, 0.21 mol) was added CH₂Cl₂ (500mL) and DMF (2 drops) at room temperature. Oxalyl chloride (32 g, 0.25mol) was added dropwise in 0.5 h and stirred for 2 d. The volatiles wereremoved in vacuo to a volume of 150 mL to give the acid chloride andCH₂Cl₂. To a mixture of ice (500 mL) and NH₄OH (29%; 100 mL) was addedthe CH₂Cl₂ solution during 15 min. The resulting solids were collected,washed with CH₂Cl₂, and dried in vacuo. The solids were slurried in H₂Ofor 1 h. The solids were collected by filtration, washed in water andacetone, and dried in vacuo to give 7 (48 g; 92%): mp 213-216° C.

Example 6 Preparation of Compound 8

[1373] To a suspension of 7 (11 g, 45 mmol) in THF (50 mL) was addedBH₃-THF (1M, 22.5 mL, 22.5 mmol). The resulting solution was heatedunder reflux overnight. The reaction was cooled in an ice bath andMeOH—HCl (60 mL) was slowly added dropwise. The resulting precipitatewas filtered and dried to give 8 (10.8 g, 88%) as a white solid: mp256-262° C. dec.; ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (bs, 3H), 7.79 (d,2H), 7.32 (d, 2H), 3.98 (s, 2H).

Example 7 Preparation of Compound 9

[1374] To compound 1 (7.63 g, 40.4 mmol) was added compound 8 (10.8 g,40.4 mmol), water (123 mL), and Hunig's base (14 mL, 81 mmol). Themixture was heated to reflux for 5 h and stirred overnight at roomtemperature to give a pale yellow solution. An additional quantity ofwater (150 mL) was added, refluxed for 3 h, then cooled overnight. Apale yellow solid was formed which was filtered, washed with water,rinsed with EtOH (2×), and dried in vacuo to give yield 9 (13.3 g, 80%):

[1375]¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (bs, 1H), 8.28 (s, 1H), 7.68 (d,2H), 7.50 (d, 2H), 5.08 (bs, 1H), 4.50 (d, 2H).

Example 8 Preparation of Compound 10

[1376] To compound 9 (12.2 g, 31.7 mmol) was added K₂CO₃ (35 g, 0.25mol), 2-iodopropane (13 g, 0.13 mol) and DMSO (210 mL). The reactionmixture was stirred under N₂ at room temperature overnight, then pouredinto H₂O (1.5 L) and stirred for 2 d. The precipitate was collected asan off-white solid and washed with Et₂O. The aqueous layer was extractedwith EtOAc (2×) and the combined organic phases were washed with brine,dried over Na₂SO₄, filtered, and evaporated to give an off-white foam(6.4 g). This off-white foam was combined with the precipitate andwashed with Et₂O to give 10 (11.0 g): ¹H NMR (300 MHz, DMSO-d₆) δ 8.91(m, 1H), 8.38 (s, 1H), 7.74 (d, 2H), 7.21 (d, 2H), 5.11 (bs, 1H), 4.68(m, 1H), 4.60 (d, 2H), 1.48 (d, 6H).

Example 9 Preparation of Compound 11

[1377] Compound 10 (1.52 g, 3.55 mmol), trans-1,4-diaminocyclohexane(6.35 g, 55.60 mmol), and EtOH (18 mL) were placed in a sealed tube. Thereaction mixture was heated at 120-190° C. for 24 h. The reaction wasthen allowed to cool to room temperature. The reaction mixture wasfiltered and the filtrate evaporated. The residue was purified by columnchromatography, and dried in vacuo for 16 h to yield 11 (1.60 g, 89%) asa yellow sticky oil: ¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, 2H), 7.44 (s,1H), 7.08 (d, 2H), 6.14 (br, 1H), 4.75-4.63 (m, 2H), 4.63-4.54 (m, 2H),3.75-3.63 (m, 1H), 2.72-2.57 (m, 2H), 2.18-2.00 (m, 2H), 2.00-1.75 (m,4H), 1.54 (d, 6H), 1.39-1.00 (m, 3H); API MS m/z=506 [C₂₁H₂₈IN₇+H]⁺.

Example 10 Preparation of Compound 12

[1378] To compound 11 (0.133 g, 0.26 mmol) was added DME (2.5 mL) and3-thiopheneboronic acid (0.12 g, 0.97 mmol) in a round-bottomed flaskand equipped with a condenser purged with argon. To this was added DME(3 mL) followed by tris(dibenzylidoneacetone)dipalladium (0.01 g, 0.01mmol) and PPh₃ (0.04 g, 0.15 mmol). Na₂CO₃ (2M, 0.6 mL) and DME (1 mL)was added to the reaction mixture and the reaction mixture was allowedto reflux for 18.5 h, then stirred at room temperature under argon for46 h. The reaction mixture was diluted with H₂O and extracted withCH₂Cl₂. The combined organic phases were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by column chromatography to yield 12 (0.050 g, 41%) as a tansolid: ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.50 (m, 4H), 7.44-7.35 (m, 3H),6.02 (br, 1H), 4.78 (d, 2H), 4.69-4.54 (m, 2H), 3.75 (br, 1H), 2.69 (br,1H), 2.15 (br, 2H), 1.88 (br, 3H), 1.54 (d, 7H), 1.33-0.97 (m, 4H); APIMS m/z=462 [C₂₅H₃₁N₇S+H]⁺.

Example 11 Preparation of Compound 13

[1379] DME (3 mL), tris(dibenzylidoneacetone)dipalladium (0.01 g, 0.01mmol), and PPh₃ (0.04 g, 0.15 mmol) were placed in a round-bottomedflask fitted with a condenser and maintained under argon. Compound 11(0.13 g, 0.26 mmol), and 4-methylbenzeneboronic acid (0.13 g, 0.98 mmol)dissolved in Na₂CO₃ (2M, 0.6 mL) and DME (1 mL) were added to thereaction mixture. The reaction mixture was refluxed for 19.5 h andstirred at room temperature for 4 h. The reaction mixture was dilutedwith water and extracted with CH₂Cl₂. The combined organic phases werewashed with brine, dried over anhydrous Na₂SO₄, and evaporated. Thecrude product was purified by column chromatography and dried in vacuofor 22 h to yield the desired product 13 (54 mg, 44%) as an off-whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.41 (m, 7H), 7.23 (s, 1H), 5.92(br, 1H), 4.83 (d, 2H), 4.74-4.58 (m, 2H), 3.77 (br, 1H), 2.70 (br, 1H),2.40 (s, 3H), 2.16 (d, 3H), 1.88 (d, 3H), 1.55 (d, 7H), 1.33-0.97 (m,4H); API MS m/z=470 [C₂₈H₃₅N₇+H]⁺.

Example 12 Preparation of Compound 14

[1380] DME (3 mL), tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01mmol), and PPh₃ (0.04 g, 0.15 mmol) were placed in a round-bottomedflask with a condenser under argon. Compound 11(0.13 g, 0.25 mmol) and3-chloro-4-fluoroboronic acid (0.15 g, 0.88 mmol) were dissolved inNa₂CO₃ (2M, 0.6 mL) and DME (1 mL) were added to the reaction mixture,refluxed for 19 h then stirred at room temperature for 2 h. The reactionmixture was diluted with water and extracted with CH₂Cl₂. The combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄, andevaporated. The crude product was purified by repeated columnchromatography to yield 14 (0.019 g, 15%): ¹H NMR (300 MHz, CDCl₃) δ7.59-7.53 (m, 1H), 7.47-7.35 (m, 4H), 7.26-7.14 (m, 3H), 5.81 (br, 1H),4.81 (d, 2H), 4.72-4.54 (m, 2H), 3.72 (br, 1H), 2.69 (br, 1H), 2.21-2.03(m, 3H), 1.94-1.78 (m, 3H), 1.54 (d, 6H), 1.33-1.12 (m, 4H); API MSm/z=508 [C₂₇H₃₁ClFN₇+H]⁺.

Example 13 Preparation of Compound 16

[1381] A solution of 15 (2.5 g, 15.8 mmol) and ether was cooled to −78°C. In a separate flask, n-BuLi (15.8 mmol) was also cooled to −78° C.The solution of 15 was added to the n-BuLi solution via cannula to givea dark red solution. The reaction mixture was stirred for 5 min prior tothe rapid addition of (n-Bu)₃SnCl (6.2 g, 19 mmol). The resulting brightyellow solution was stirred at −78° C. for 2 h, allowed to warm to roomtemperature, and stirred for another 10 min. The solution was thendiluted with H₂O (80 mL) and extracted with ethyl acetate (3×50 mL). Theorganic extracts were combined, washed with brine, dried over Na₂SO₄,filtered, and concentrated in vacuo to yield the crude product as ayellow oil. Purification by column chromatography gave the product 16(4.89 g, 84%) as a pale yellow liquid:

[1382]¹H NMR (300 MHz, CDCl₃) δ 8.72 (d, 1H), 7.48-7.46 (m, 1H),7.40-7.38 (m, 1H), 7.11-7.09 (m, 1H), 1.61-1.50 (m, 6H), 1.38-1.26 (m,6H), 1.14-1.09 (m, 6H), 0.97-0.77 (t, 9H).

Example 14 Preparation of Compound 17

[1383] To compound 16 (0.18 g, 0.48 mmol) was added compound 4 (0.14 g,0.33 mmol), Pd(PPh₃)₄ (0.05 g, 0.49 mmol), and toluene (10 mL) in asealed tube under an argon atmosphere. The solution was degassed withargon and heated at 135° C. in an oil bath for 3 h. The solution wascooled to room temperature, diluted with saturated NaHCO₃, and extractedwith CH₂Cl₂ (3×30 mL). The organic layer was washed with brine, driedover Na₂SO₄, and concentrated in vacuo to give a light brown oil. Theresidue was purified by flash column chromatography using MeOH/CH₂Cl₂(10%) to afford 17 as a white solid. The sample was dissolved intohexane/CH₂Cl₂/MeOH and then precipitated with diethyl ether, filtered,and rinsed several times with ether to provide in 17 (30.3 mg): mp95-100° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, 1H), 7.96 (d, 2H),7.77-7.69 (m, 2H), 7.49-7.45 (m, 3H), 7.24-7.20 (m, 1H), 5.99 (s, 1H),5.11 (s, 1H), 4.88-4.83 (m, 3H), 4.65-4.56 (m, 1H), 3.91-3.80 (m, 2H),3.65-3.60 (m, 1H), 1.66-1.52 (m, 8H), 1.05-0.99 (t, 3H); IR (KBr) 3411,2968, 1601, 1489 cm⁻¹; CI MS m/z=432 [C₂₄H₂₉N₇+H]⁺.

Example 15 Preparation of Compound 19

[1384] To a solution of n-BuLi (2.5M hexane solution, 10.9 mL, 27.4mmol) in ethyl ether 28 mL at −78° C. was added 2-bromopyridine (4.33 g,27.4 mmol) in ethyl ether (15 mL). After stirring for 30 min, a solutionof trimethylstannylchloride (6.0 g, 30 mmol) in THF (10 mL) was added.Stirring was continued at −78° C. for 2 h and the mixture was thenwarmed up to room temperature and filtered. The precipitate was washedwith ether and the combined the ether filtrates were concentrated togive the crude product: ¹H NMR (500 Hz, CDCl₃) δ 8.69-8.68 (d, 1H),7.47-7.07 (m, 3H), 0.30 (s, 9H).

Example 16 Preparation of Compound 21

[1385] A mixture of 4-bromobenzonitrile (1.68 g, 9.2 mmol), crude2-trimethylstannylpyridine (3.33 g, 13.8 mmol), and PdCl₂(PPh₃)₂ (321mg, 0.46 mmol) in DMF (25 mL) was heated at 150-155° C. in pressure tubefor 24 h. The DMF was distilled off under reduced pressure and theresidue was filtered through a short column of basic alumina and washedwith ethyl acetate and then concentrated. Flash chromatography of theresidue on silica gel gave the product (41%) as a white solid: mp99-100° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.74 (dd, J₁=1 Hz, J₂=1.7 Hz, 1H),8.12 (d, J=8.6 Hz, 2H), 7.83-7.76 (m, 4H), 7.32 (m, 1H).

Example 17 Preparation of Compound 22

[1386] To LiAlH₄ (8 mmol) in THF (25 mL) was added 21 (0.96 g, 5.3 mmol)in THF (15 mL) slowly while the flask was cooled with ice. The mixturewas stirred at room temperature for 10-30 min then stirred at reflux for4 h under nitrogen. The mixture was cooled in an ice bath and aqueoussodium hydroxide solution (0.5 mL, 10%) was added. The mixture wasstirred until the residue became white and the solid was filtered andwashed with methylene chloride (4×5 mL). The methylene chloride solutionwas dried with anhydrous sodium sulfate, concentrated, and the crudeproduct was chromatographed on silica gel to give the product as ayellow liquid. A small amount of ethanol was added and the pure amine 22was obtained as a white solid (74%) after filtration: mp 114-117° C.; ¹HNMR (500 Hz, CDCl₃) δ 8.66 (d, J=4.4 Hz, 1H), 7.94 (d, J=8.1 Hz, 2H),7.70 (m, 2H), 7.39 (d, J=8.0 Hz), 7.19 (m, 1H), 3.90 (s, 2H), 1.98 (s,2H).

Example 18 Preparation of Compound 23

[1387] A mixture of 2,6-dichloropurine (1, 0.19 g, 1 mmol), amine 22(0.39 g, 2.15 mmol) in ethanol (13 mL), and water (3.4 mL) was heated at100-110° C. under nitrogen for 24 h and then it was cooled to roomtemperature. The mixture was concentrated and water (5 mL) was added. Asolid was filtered and washed with water (2×5 mL) and dried under vacuumto give the product (93%) as yellow solid: mp 260° C. (dec); ¹H NMR (500Hz, DMSO-d₆) δ 12.4 (bs, 1H), 8.76 (m, J=1 Hz, 1 H), 8.28 (s, 1H), 8.16(d, J=8.1 Hz, 2H), 8.03 (d, J=7.8 Hz, 1H), 7.97 (m, 1H), 7.58 (d=8.6 Hz,2H), 7.45 (m, 1H), 4.82 (s, 2H).

Example 19 Preparation of Compound 24

[1388] To the solution of compound 23 (0.33 g, 1 mmol) in DMSO (5.2 mL),added potassium carbonate (0.7 g, 5 mmol) and 2-iodopropane (0.5 g, 3mmol). The mixture was stirred at ambient temperature under nitrogen for24 h and poured into ice water (30 mL). After filtration, the solid waswashed with water (4×5 mL), dried under vacuum to give the crude productas a yellow solid. Flash column chromatography of the crude product onsilica gel and recrystallization provided the pure product (76%) aswhite crystals: mp 178-179° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.68 (m, 1H),7.96 (d, J=8 Hz, 2H), 7.76-7.70 (m, 2H), 7.73 (s, 1H), 7.47 (d, J=8 Hz,2H), 7.22 (m, 1H), 4.89 (s, 1H), 4.79 (m, 1H), 1.54 (d, J=6.8 Hz, 6H);CI MS m/z=379 [C₂₀H₁₉ClN₆+H]⁺. Anal. Calcd. for C₂₀H₁₉ClN₆: C, 63.41; H,5.05; N, 22.18. Found: C, 63.07; H, 5.01; N, 22.01.

Example 20 Preparation of Compound 17

[1389] To compound 24 (0.7 g, 1.8 mmol) was added (R)-(−)-2amino-1-butanol (3.5 g, 3.9 mmol) stirred in a sealed tube for 2 h at190° C. The reaction mixture was allowed to cool and then waspartitioned between EtOAc and brine. The EtOAc was separated, washedwith saturated brine (4×), dried with Na₂SO₄, and concentrated. Theproduct was air dried to give an oil, then dissolved in EtOAc. The EtOAcsolution was cooled again, and the precipitate collected, washed withcold EtOAc (2×), air dried, and heated in vacuo for 2 h to give 17 (0.54g, 67%): mp 98-100° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.00-7.85 (m, 2H),7.75-7.55 (m, 2H), 7.50-7.35 (m, 3H), 7.30-7.15 (m, 1H), 6.40-6.20 (bs,1H), 5.00-4.82 (m, 1H), 4.80-4.68 (bs, 3H), 4.60 (heptuplet, 1H),3.98-3.70 (m, 2H), 3.70-3.54 (dd, 1H), 2.10 (bs, 1H), 1.75-1.53 (m, 2H),1.51 (d, 6H), 1.00 (t, 3H); IR (KBr) 3406, 2969, 1601, 1490, 1389, 1254,779 cm⁻1; API MS m/z=432 [C₂₄H₂₉N₇O+H]⁺.

Example 21 Preparation of Compound 25

[1390] To compound 4 (0.14 g, 0.33 mmol) was added3-(tributylstannyl)pyridine (0.15 g, 0.33 mmol), Pd(PPh₃)₄ (0.06 g, 0.41mmol), and toluene (10 mL). The solution was degassed with argon for 8min in a sealed tube, and heated in an oil bath for 3 h at 130° C. Thecooled reaction mixture was diluted with saturated NaHCO₃ and extractedwith CH₂Cl₂ (3×50 mL). The combined organic extracts were washed withbrine and dried over Na₂SO₄. The reaction mixture was purified by columnchromatography on silica gel to give the desired coupling product. Theproduct was dissolved in acetonitrile and washed with hexane (3×10 mL)to remove a portion of the tin contaminants. The reaction mixture wasagain purified by column chromatography on reversed phase silica gel togive compound 25 (0.04 g): ¹H NMR (300 MHz, CDCl₃) δ 8.83 (s, 1H), 8.58(d, 1H), 7.88-7.83 (m, 1H), 7.56-7.46 (m, 5H), 7.38-7.33 (m, 1H), 5.99(s, 1H), 5.11 (s, 1H), 4.90-4.83 (m, 2H), 4.63-4.56 (m, 1H), 3.92-3.81(m, 2H), 3.67-3.60 (m, 1H), 1.69-1.49 (m, 8H), 1.05-1.00 (t, 3H); CI MSm/z=432 [C₂₄H₂₉N₇O+H]⁺.

Example 22 Preparation of Compound 27

[1391] A mixture of diethyl(3-pyridyl)borane (26, 540 mg, 3.67 mmol),4-bromobenzonitrile (803 mg, 4.41 mmol) and Pd(PPh₃)₄ (144 mg, 0.13mmol) in toluene (9 mL), ethanol (1.3 mL) and 2M aqueous sodiumcarbonate solution (4.1 mL, 8.2 mmol) was heated at 90-100° C. undernitrogen for 27 h. The mixture was cooled to room temperature and water(10 mL) was added. The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (2×20 mL). The combined organic layerswere washed with brine (2×15 mL) and dried over anhydrous sodiumsulfate. Flash chromatography of the crude product on silica gave theproduct as a white solid (80%): mp 95-96° C.

Example 23 An Alternative Preparation of 27 is Described Below

[1392] A flask charged with 4-bromobenzonitrile (360 mg, 2.0 mmol),bis(pinacolato)diboron (560 mg, 2.2 mmol), potassium acetate (590 mg,6.0 mmol) and PdCl₂(dppf) (49 mg, 0.06 mmol) was flushed with nitrogenand DMF (12 mL) was added. The mixture was heated at 80-85° C. for 4 hand then cooled to room temperature at which time PdCl₂(dppi) (49 mg,0.06 mmol), 3-bromopyridine (385 6L, 3.40 mmol), and 2M aqueous sodiumcarbonate solution (5 mL, 10 mmol) was added. The mixture was stirred at80-85° C. for 24 h and extracted with ethyl ether (3×30 mL) and thenwashed with brine (3×15 mL) and dried with anhydrous sodium sulfate.Flash chromatography of the crude product on silica gel gave the productas white crystals (56%): mp 96-97° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.55(dd, J₁=1 Hz, J₂=1.4 Hz, 1H), 8.66 (m, 1H), 7.90-7.87 (m, 1H), 7.77 (d,J=7.8 Hz, 2H), 7.69 (d, J=8.8 Hz, 2H), 7.42 (m, 1H).

Example 24 Preparation of Compound 28

[1393] To LiAlH₄ (8 mmol) in THF (25 mL) was added 27 (0.96 g, 5.3 mmol)in THF (25 mL) slowly while the flask was cooled with ice. The mixturewas stirred at room temperature for 10-30 min then stirred at reflux for4 h under nitrogen. The mixture was cooled in an ice bath and aqueoussodium hydroxide solution (0.5 mL, 10%) was added. The mixture wasstirred until the residue became white and the solid was filtered andwashed with methylene chloride (4×5 mL). The methylene chloride solutionwas dried with anhydrous sodium sulfate, concentrated, and the crudeproduct was chromatographed on silica gel to give the product as ayellow liquid. A small amount of ethanol was added and the pure amine 28was obtained as a white solid (46%) after filtration: mp 94-96° C.; ¹HNMR (500 Hz, CDCl₃) δ 8.74 (d, J=2.4 Hz, 1H), 8.48 (dd, J₁=1.5 Hz,J₂=4.7 Hz, 1H), 7.77 (m, 1H), 7.45 (d, J=8.10 Hz, 2H), 7.33 (d, J=8.0Hz, 2H), 7.25 (m, 1H), 3.83 (s, 2H), 2.25 (s, 2H).

Example 25 Preparation of Compound 29

[1394] A mixture of 2,6-dichloropurine (1, 0.19 g, 1 mmol), amine 28(0.4 g, 2.15 mmol) in ethanol (13 mL), water (3 mL) was heated at100-110° C. under nitrogen for 24 h and then it was cooled to roomtemperature. The mixture was concentrated and water (5 mL) was added. Asolid was filtered and washed with water (2×5 mL) and dried under vacuumto give the product (92%) as a yellow solid: mp 219° C. (dec); ¹H NMR(500 Hz, DMSO-d₆) δ 13.2 (bs, 1H), 8.99 (s, 1H), 8.66 (d, J=3.5 Hz, 1H),8.28 (s, 1H), 8.16 (d, J=7.3 Hz, 1H), 7.80 (d, J=7.6 Hz, 2H), 7.60-7.57(m, 3H).

Example 26 Preparation of Compound 30

[1395] To a solution of 29 (0.3 g, 1 mmol) in DMSO (5 mL), was addedpotassium carbonate (0.7 g, 5 mmol) and 2-iodopropane (0.5 g, 3 mmol).The mixture was stirred at ambient temperature under nitrogen for 24 hand poured into ice water (30 mL). After filtration, the solid waswashed with water (4×5 mL), dried under vacuum to give the crude productas a yellow solid. Flash column chromatography of the crude product onsilica gel and recrystallization provided the pure product (76%) aswhite crystals: mp 178-179° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.82 (d, J=1.3Hz, 1H), 8.59-8.58 (m, 1H), 7.86-7.84 (m, 1H), 7.72 (s, 1H), 7.56-7.48(m, 4H), 7.37-7.34 (m, 1H), 4.88 (s, 2H), 4.82 (m, 1H), 1.56 (d, J=0.7Hz, 3H), 1.55 (d, J=0.8 Hz, 3H); CI MS m/z=379 [C₂₀H₁₉ClN₆+H]⁺. Anal.Calcd. for C₂₀H₁₉ClN₆: C, 63.41; H, 5.05; N, 22.18. Found: C, 63.24; H,4.97; N, 21.93.

Example 27 Preparation of Compound 32

[1396] To a mixture of 4 (0.05 g, 0.11 mmol) was added4-(tributylstannyl)pyridine (0.06 g, 0.16 mmol), Pd(PPh₃)₄ (0.02 g, 0.02mmol), and toluene (2.5 mL). The reaction mixture was degassed andheated in a sealed tube at 125° C. for 3 h. The reaction mixture wascooled to room temperature then saturated NaHCO₃ (30 mL) was addedfollowed by extraction with CH₂Cl₂ (3×30). The organic layer was washedwith brine (50 mL), dried with MgSO₄, and concentrated. The reactionmixture was purified by column chromatography on silica gel to give 32:

[1397]¹H NMR (300 MHz, CDCl₃) δ 8.65 (s, 2H), 7.60-7.57 (m, 2H),7.49-7.45 (m, 5H), 6.20 (s, 1H), 4.93 (d, 1H), 4.84 (s, 2H), 4.65-4.57(m, 1H), 3.92-3.80 (m, 2H), 3.68-3.51 (m, 1H), 1.68-1.58 (m, 2H), 1.52(d, 6H), 1.05-0.99 (t, 3H).

Example 28 Preparation of Compound 33

[1398] To compound 4 (0.18 g, 0.43 mmol) was added 4-vinylphenylboronicacid (0.19 g, 1.28 mmol), Pd(PPh₃)₄ (0.09 g, 0.08 mmol), Na₂CO₃ (2M,0.85 mL), was added toluene (5 mL). The mixture was degassed with argonfor 10 min. The resulting solution was heated in a sealed tube at 135°C. for 4.5 h. The cooled solution was diluted with water and extractedwith CH₂Cl₂ (3×50 mL). The combined organic extracts were washed withbrine and dried over Na₂SO₄. The solution was purified by flash columnchromatography (2×) on silica gel to give the desired product 33 as ayellow solid (0.09 g): mp 130-131° C.; ¹H NMR (300 MHz, CDCl₃) δ7.57-7.42 (m, 9H), 6.80-6.70 (dd, 1H), 5.98 (s, 1H), 5.79 (d, 1H), 5.27(d, 1H), 4.88 (d, 1H), 4.84-4.72 (m, 2H), 4.63-4.56 (m, 1H), 3.92-3.81(m, 2H), 3.66-3.60 (m, 1H), 1.68-1.52 (m, 8H), 1.05-1.00 (t, 3H); IR(CH₂Cl₂) 3293, 2968, 1601, 1489, 1390 cm⁻¹; CI MS m/z=457[C₂₇H₃₂N₆O+H]⁺.

Example 29 Preparation of Compound 34

[1399] To compound 33 (0.008 g, 0.016 mmol) was added OSO₄ (0.007 g,0.026 mmol), pyridine (0.08 mL), and toluene (0.75 mL). The reactionmixture was stirred at room temperature in the dark for 1 h,concentrated in vacuo, and then slurried in methanol/water (9:1). Sodiummetabisulfite (0.07 g) was added and the reaction was stirred for 1 h.The mixture was washed with brine, extracted with CH₂Cl₂ (3×10 mL),dried over Na₂SO₄, and concentrated. The product was purified by columnchromatography on silica gel to give compound 34 (0.003 g) as a tansolid:

[1400]¹H NMR (300 MHz, CDCl₃) δ 7.51 (s, 1H), 7.43-7.35 (m, 6H),7.25-7.22 (m, 2H), 6.51 (s, 1H), 4.98 (d, 1H), 4.35-4.25 (m, 2H),4.64-4.54 (m, 1H), 3.93-3.80 (m, 3H), 3.74-3.59 (m, 3H), 1.68-1.58 (m,2H), 1.52 (d, 6H), 1.06-0.99 (t, 3H).

Example 30 Preparation of Compound 36

[1401] To compound 4 (0.12 g, 0.27 mmol) was added 3-aminophenylboronicacid hydrochloride (0.12 g, 0.69 mmol), and Pd(PPh₃)₄ (0.09 g, 0.75mmol) in a sealed tube filled with argon. To this mixture was addedtoluene (5 mL) and Na₂CO₃ (2M, 0.55 mL). The resulting solution wasdegassed with argon for 5 min and placed in a 130° C. oil bath for 6 h.The cooled solution was diluted with water and extracted with CH₂Cl₂(3×50 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, and concentrated. The solution was purified by columnchromatography on silica gel to yield 36 (0.04 g, 36%): ¹H NMR (300 MHz,CDCl₃) δ 7.52-7.46 (m, 3H), 7.39 (d, 2H), 7.23-7.18 (m, 1H), 6.96 (d,1H), 6.88 (t, 1H), 6.68-6.66 (m, 1H), 6.12 (s, 1H), 4.90 (d, 1H), 4.79(s, 2H), 4.62-4.57 (m, 1H), 3.92-3.76 (m, 4H), 3.66-3.60 (m, 1H),1.65-1.48 (m, 8H), 1.04-0.99 (t, 3H); CI MS m/z=446 [C₂₅H₃₁N₇O+H]⁺.

Example 31 Preparation of Compound 38

[1402] To a suspension of Pd(PPh₃)₄ (0.02 g, 0.01 mmol) in anhydrous DME(8 mL) was added 4 (0.12 g, 0.27 mmol) and the mixture stirred at roomtemperature for 10 min. To this solution was added3-(trifluoromethyl)phenylboronic acid (37; 0.12 g, 0.65 mmol) in aminimum of EtOH, followed by Na₂CO₃ (2M, 0.27 mL), and the resultingmixture was heated at reflux for 20 h. The cooled reaction mixture wasdiluted with water and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated. The reaction mixture was purified by column chromatographyon normal phase silica gel followed by reversed phase columnchromatography to obtain 38 (0.04 g, 33%) as an off white solid: mp60-67° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.81 (s, 1H), 7.74 (d, 1H),7.58-7.45 (m, 7H), 5.98 (s, 1H), 4.90-4.83 (m, 3H), 4.63-4.59 (m, 1H),3.90-3.81 (m, 2H), 3.66-3.60 (m, 1H), 1.68-1.51 (m, 8H), 1.05-1.00 (t,3H); IR (KBr) 3406, 2969, 1602, 1489, 1335 cm⁻¹; CI MS m/z=499[C₂₆H₂₉FN₇O+H]⁺.

Example 32 Preparation of Compound 40

[1403] A mixture of 4 (0.13 g, 0.31 mmol), 2-naphthaleneboronic acid(39; 0.11 g, 0.62 mmol) and Pd(PPh₃)₄ (0.09 g, 0.08 mmol) was placed ina sealed tube that was filled with argon. To the mixture was addedtoluene (5 mL) and Na₂CO₃ (2M, 0.62 mL). The tube was quickly sealed andheated at 125° C. in an oil bath for 6 h. The cooled solution wasdiluted with water and extracted with CH₂Cl₂ (3×50 mL). The organiclayers were washed with brine, dried over Na₂SO₄, and concentrated. Thereaction mixture was purified by column chromatography on normal phasesilica gel, followed by reversed phase chromatography to give 40 (0.04g, 28%): mp 70-75° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.02 (s, 1H), 7.92-7.84(m, 3H), 7.74-7.67 (m, 3H), 7.51-7.44 (m, 5H), 5.96 (s, 1H), 4.89-4.84(m, 3H), 4.66-4.57 (m, 1H), 3.93-3.82 (m, 2H), 3.67-3.61 (m, 1H),1.76-1.50 (m, 8H), 1.06-1.01 (t, 3H); IR (KBr) 3422, 2927, 1601, 1491,1388 cm⁻¹.

Example 33 Preparation of Compound 43

[1404] To compound 4 (0.14 g, 0.33 mmol) was added4-methoxyphenylboronic acid (42, 0.11 g, 0.71 mmol), Pd(PPh₃)₄ (0.10 g,0.087 mmol), Na₂CO₃ (2M, 0.66 mL), and toluene (7 mL). The solution wasdegassed for 8 min with argon and heated in an oil bath at 125° C. for 6h. The cooled solution was 10 diluted with water and extracted withCH₂Cl₂ (3×50 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The reaction mixture waspurified by normal phase column chromatography followed by reversedphase chromatography to give 43 (0.05 g, 28%) as a white solid: mp128-130° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.52-7.50 (m, 5H), 7.41 (d, 2H),6.97 (d, 2H), 5.93 (s, 1H), 4.89-4.79 (m, 3H), 4.63-4.56 (m, 1H),3.92-3.81 (m, 5H), 3.67-3.60 (m, 1H), 1.68-1.49 (m, 8H), 1.05-1.00 (t,3H); IR (KBr) 3417, 2931, 1610, 1499, 1389 cm⁻¹; CI MS m/z=461[C₂₆H₃₂N₆O₂+H]⁺.

Example 34 Preparation of Compound 45

[1405] To a solution of s-BuLi (5 mL, 6.24 mmol) and TMEDA (1 mL) inanhydrous THF (35 mL) at −75° C. under argon was added dropwise asolution of N,N-diethylbenzamide (0.98 g, 5.57 mmol) in THF (5 mL). Themixture was stirred for 50 min and then treated with trimethylborate (2mL, 17 mmol). The solution was allowed to warm to room temperatureovernight. The colorless solution was cooled to 0° C. and acidified topH=6 with 2N HCl. The THF was removed in vacuo and the residue wasdiluted with water. This was extracted with CH₂Cl₂ (3×50 mL) and thecombined organic layers were washed with brine, dried over Na₂SO₄,concentrated in vacuo, followed by removal of trace solvent on thevacuum pump to give 45 as an off-white foamy solid: ¹H NMR (300 MHz,CD₃OD) δ 7.67-7.39 (m, 4H), 3.88-3.69 (q, 4H), 1.41-1.30 (t, 6H).

Example 35 Preparation of Compound 46

[1406] To compound 4 (0.14 g, 0.31 mmol) was added2-(diethylcarbamoyl)phenylboronic acid (45, 0.29 g, 1.31 mmol),Pd(PPh₃)₄ (0.1 g, 0.09 mmol), Na₂CO₃ (2M, 0.63 mL), toluene (5 mL), andthe mixture degassed with argon for 10 min. The mixture was heated in anoil bath for 5 h at 135° C. The cooled solution was diluted with waterand extracted with CH₂Cl₂ (3×50 mL). The organic layers were combined,washed with brine, dried over Na₂CO₃, and concentrated. The reactionmixture was purified by normal phase column chromatography on silicagel, followed by reversed phase chromatography to give 46 (0.03 g, 18%)as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 7.49-7.36 (m, 9H), 6.18 (s,1H), 4.93 (d, 1H), 4.78 (s, 2H), 4.64-4.55 (m, 1H), 3.92-3.60 (m, 4H),3.06-2.92 (m, 2H), 2.69-2.64 (m, 1H), 1.68-1.51 (m, 8H), 1.04-0.99 (t,3H), 0.91-0.86 (t, 3H), 0.77-0.72 (t, 3H); CI MS m/z 530[C₃₀H₃₉N₇O₂+H]⁺.

Example 36 Preparation of Compound 48

[1407] To a suspension of Pd(PPh₃)₄ (0.08 g, 0.69 mmol) in DME was added4 (0.129 g, 0.30 mmol) and the mixture stirred for 10 min at roomtemperature. To this was added 3-nitrophenylboronic acid (47, 0.157 g,0.94 mmol) and Na₂CO₃ (2 M, 0.59 mL). The solution was heated at refluxunder argon overnight. The cooled solution was diluted with water andextracted with CH₂Cl₂ (3×50 mL). The organic layers were combined,washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Thesolution was purified by flash column chromatography on silica gel togive 48 (0.04 g, 29%) as a bright yellow solid: mp 73-77° C.; ¹H NMR(300 MHz, CDCl₃) δ 8.43 (s, 1H), 8.20 (d, 1H), 7.89 (d, 1H), 7.63-7.43(m, 6H), 6.01 (s, 1H), 4.95-4.76 (m, 3H), 4.68-4.58 (m, 1H), 3.98-3.80(m, 2H), 3.68-3.60 (m, 1H), 1.71-1.40 (m, 8H), 1.02-0.98 (t, 3H); IR(KBr) 3405, 2930, 1713, 1602, 1490, 1351 cm⁻¹ CI MS m/z=476[C₂₅H₂₉N₇O₃+H]⁺.

Example 37 Preparation of Compound 50

[1408] To a suspension of Pd(PPh₃)₄ (0.09 g, 0.08 mmol) in DME (5 mL)was added 4 (0.14 g, 0.32 mmol) and the mixture stirred at roomtemperature for 15 min. To this was added benzo[b]furan-2-boronic acid(49, 0.153 g, 0.94 mmol) and Na₂CO₃ (2 M, 0.63 mL). The solution washeated at reflux under argon overnight. The reaction mixture was cooled,diluted with water, extracted with CH₂Cl₂ (3×50 mL). The organic layerswere combined, washed with brine, dried over Na₂SO₄, and concentrated invacuo. The solution was purified by flash column chromatography onsilica gel followed by flash column chromatography on reversed phasesilica to give 50 (0.09 g, 60%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 7.82 (d, 2H), 7.58-7.42 (m, 5H), 7.30-7.19 (m, 2H), 7.01 (s,1H), 6.11 (s, 1H), 4.91 (d, 1H), 4.81 (s, 2H), 4.62-4.58 (m, 1H),3.92-3.80 (m, 2H), 3.66-3.60 (m, 1H), 1.66-1.48 (m, 8H), 1.04-0.99 (t,3H); CI MS m/z=471 [C₂₇H₃₀N₆O₂+H]⁺.

Example 38 Preparation of Compound 52

[1409] To compound 4 (0.46 g, 1.20 mmol) was added1-amino-1-cyclopentanemethanol (51, 1.0 g, 8.61 mmol) and EtOH (2 mL)and the mixture was heated in an oil bath at 150° C. for 60 h. The brownsolution was cooled and heated again at 150° C. for 48 h. The reactionmixture was cooled and concentrated in vacuo. The reaction mixture waspurified by flash column chromatography on silica gel to give 52 (0.39g, 71%) as a tan solid: ¹H NMR (300 MHz, CDCl₃) δ 7.48-7.40 (m, 3H),7.29-7.20 (m, 2H), 6.88 (s, 1H), 6.25 (s, 1H), 5.10 (s, 1H), 4.72 (s,2H), 4.63-4.51 (m, 1H), 3.78 (s, 2H), 2.10-1.65 (m, 8H), 1.54 (d, 6H);CI MS m/z=459 [C₂₁H₂₇BrN₆O+H]⁺.

Example 39 Preparation of Compound 53

[1410] To a suspension of Pd(PPh₃)₄ (0.07 g, 0.06 mmol) in DME (5 mL)was added 52 (0.102 g, 0.22 mmol) and stirred at room temperature for 15min. To this was added phenylboronic acid (0.098 g, 0.80 mmol) andNa₂CO₃ (2 M, 0.44 mL). The solution was heated at reflux under argon for18 h. The reaction mixture was diluted with water, extracted with CH₂Cl₂(3×50 mL), washed with brine, and dried over Na₂SO₄. The solution waspurified by flash column chromatography on silica gel followed by flashcolumn chromatography on reversed phase silica gel to give 53 (0.02 g,20%): ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.31 (m, 10H), 6.95 (s, 1H), 5.95(s, 1H), 5.10 (s, 1H), 4.79 (s, 2H), 4.61-4.52 (m, 1H), 3.76 (s, 2H),2.01-1.61 (m, 8H), 1.54 (d, 6H); CI MS m/z=457 [C₂₇H₃₂N₆O+H]⁺.

Example 40 Preparation of Compound 54

[1411] To compound 3 (0.26 g, 0.67 mmol) was addedtrans-4-aminocyclohexanol hydrochloride (0.62 g, 4.11 mmol), Et₃N (0.58mL, 4.16 mmol), and ethanol (5 mL). The mixture was heated for 5 h at135° C. in an oil bath. The temperature increased to 150° C. and heatingwas continued for a further 48 h. The solution was cooled and evaporatedto give a yellow oil: CI MS m/z=459 [C₂₁H₂₇BrN₆O+H]⁺.

Example 41 Preparation of Compound 55

[1412] To compound 3 (0.50 g, 1.31 mmol) was addedcis-1,2-diaminocyclohexane (1.57 mL, 13.1 mmol) and EtOH (4 mL). Themixture was heated in an oil bath at 150° C. for 6 h. The reactionmixture was concentrated in vacuo. The reaction mixture was purified bycolumn chromatography on silica gel to give 55 (0.49 g, 82%) as a yellowsolid: ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.40 (m, 3H), 7.23 (d, 2H), 6.21(s, 1H), 5.04 (d, 1H), 4.72 (s, 2H), 4.67-4.58 (m, 1H), 4.08-4.05 (m,1H), 3.17-3.15 (m, 1H), 2.08 (s, 2H), 1.65-1.38 (m, 14H); CI MS m/z=458[C₂₁H₂₈BrN₇+H]⁺.

Example 42 Preparation of Compound 56

[1413] To compound 55 (0.10 g, 0.22 mmol) was added2-(tributylstannyl)pyridine (0.10 g, 0.27 mmol), Pd(PPh₃)₄ (0.05 g, 0.04mmol), and toluene (5 mL). The solution was degassed with argon for 8min and heated at 135° C. for 3 h. The cooled solution was diluted withwater, extracted with CH₂Cl₂ (3×50 mL), and the combined organicextracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The solution was followed by flash column chromatography(2×) to give the desired product 56 (0.03 g, 36%) yellow crystallinesolid: ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, 1H), 7.96 (d, 2H), 7.78-7.69(m, 2H), 7.49 (s, 1H), 7.44 (d, 2H), 7.23-7.18 (m, 1H), 6.10 (s, 1H),5.10-5.00 (m, 1H), 4.83 (s, 2H), 4.69-4.60 (m, 1H), 4.20-4.10 (m, 1H),3.27-3.13 (m, 1H), 2.48 (s, 2H), 1.78-1.42 (m, 14H); CI MS m/z=457[C₂₆H₃₂N₈+H]⁺.

Example 43 Preparation of Compound 57

[1414] To compound 1 (0.50 g, 1.31 mmol) was addedtrans-1,2-diaminocyclohexane (2.52 mL, 21 mmol), and EtOH (6 mL). Thereaction mixture was placed in an oil bath and heated to 190° C. for 25h. The reaction mixture was removed from the heat and cooled to roomtemperature, concentrated for purification. The reaction mixture waspurified by column chromatography on silica gel to yield 57 (520 mg,87%) as an off white foam: ¹H NMR (300 MHz, DMSO) δ 7.95 (bs, 1H), 7.85(s, 1H), 7.50 (d, 2H), 7.34 (d, 2H), 6.17 (d, 1H), 4.70-4.40 (m, 1H),2.00-1.71 (m, 4H), 1.70-1.52 (m, 2H), 1.41 (d, 6H), 1.30-0.92 (m, 4H);API MS m/z=460 [C₂₁H₂₈N₇Br+H]⁺.

Example 44 Preparation of Compound 58

[1415] Compound 57 (0.15 g, 0.32 mmol) was added to a suspension ofPd(PPh₃)₄ (0.11 g, 0.1 mmol) in DME (7 mL) and stirred at roomtemperature for 15 min. Phenylboronic acid (0.14 g, 1.14 mmol) was addedfollowed by the Na₂CO₃ (2M, 0.62 mmol). The reaction mixture wasrefluxed under argon for 18 h and allowed to stir at room temperaturefor 51 h. It was then diluted with water, extracted with CH₂Cl₂, washedwith brine, and then extracted with CH₂Cl₂. The organic layer wasevaporated, dried over anhydrous Na₂SO₄, purified by columnchromatography, and placed in vacuo for 18 h to give 58 (0.10 g, 72%) asa white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.62-7.35 (m, 10H), 5.92 (br,1H), 4.83 (br, 2H), 4.74-4.56 (m, 2H), 3.77-3.55 (m, 1H), 2.55-2.43 (m,1H), 2.16-1.91 (m, 2H), 1.73 (br, 2H), 1.52 (d, 6H), 1.37-1.09 (m, 6H);API MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 45 Preparation of Compound 59

[1416] To compound 57 (460 mg, 1.0 mmol) in solution with CH₂Cl₂ (2 mL)was added acetic anhydride (0.44 mL, 4.6 mmol), catalytic DMAP, andpyridine (0.5 mL). The mixture was stirred at room temperature for 2.5h. The mixture was diluted with CH₂Cl₂, washed with 2N HCl, and thecombined organics were then washed with NaHCO₃. The organics were thenwashed with brine, dried over Na₂SO₄, filtered, and concentrated to give59 (472 mg, 94%) as an off white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.76(s, 1H), 7.42 (d, 2H), 7.29 (d, 2H), 4.68-4.40 (m, 1H), 4.10 (s, 3H),3.61-3.40 (m, 2H), 2.15-1.80 (m, 2H), 1.74-1.55 (m, 4H), 1.45 (d, 6H),1.35-1.05 (m, 4H); API MS m/z=500 [C₂₃H₃₀BrN₇O+H]⁺.

Example 46 Preparation of Compound 60

[1417] To a suspension of Pd(PPh₃)₄ (0.11 g, 0.1 mmol) in DME (7 mL) wasadded compound 59 (0.15 g, 0.3 mmol) and stirred at room temperature for15 min under argon. Phenylboronic acid (0.13 g, 1.06 mmol) was added,followed by Na₂CO₃ (2M, 0.62 mL). The reaction mixture was refluxedunder argon for 18 h. The reaction mixture was then diluted with H₂O,extracted with CH₂Cl₂, washed with brine, and extracted with CH₂Cl₂. Theorganic layer was dried over anhydrous Na₂SO₄, purified by columnchromatography, concentrated in vacuo for 18 h to yield 60 (61 mg, 42%):¹H NMR (300 MHz, DMSO-d₆) δ 7.96 (s, 1H), 7.72 (s, 1H), 7.51 (t, 3H),7.40-7.28 (m, 3H), 7.28-7.13 (m, 2H), 5.84 (br, 1H), 4.46 (br, 3H), 3.47(br, 2H), 1.83 (br, 1H), 1.62 (s, 4H), 1.43 (d, 6H), 0.12 (s, 3H); APIMS m/z=498 [C₂₉H₃₅N₇O+H]⁺.

Example 47 Preparation of Compound 61

[1418] To compound 3 (0.58 g, 1.53 mmol) was addedtrans-1,4-diaminocyclohexane (1.78 g, 15.6 mmol), and EtOH (4 mL). Themixture was heated in an oil bath at 150° C. for ca. 60 h. The reactionmixture was purified by column chromatography on silica gel to yield 61(0.48 g, 68%) as an off white solid: mp 122-125° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.43 (s, 1H), 7.40 (d, 2H), 7.20 (d, 2H), 6.27 (s, 1H),4.75-4.68 (m, 2H), 4.67-4.58 (m, 2H), 3.81-3.68 (m, 1H), 3.45 (s, 2H),2.88-2.75 (m, 1H), 2.18-2.05 (m, 2H), 2.05-1.89 (m, 2H), 4.52 (d, 6H),1.45-1.13 (m, 4H); CI MS m/z=459 [C₂₁H₂₈BrN₇+H]⁺.

Example 48 Preparation of Compound 62

[1419] Amine 61 (53 mg, 0.12 mmol) was dissolved in CH₂Cl₂ (2 mL) andpyridine (5 mL). Acetic anhydride (0.05 g, 0.53 mmol) and DMAP (fewcrystals) were added. The reaction mixture was allowed to stir at roomtemperature for 2.25 h. The reaction mixture was diluted with CH₂Cl₂,washed with 2N HCl, NaHCO₃, dried over MgSO₄, filtered, and evaporatedto yield 62 (0.05 g, 78%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.50-7.20 (m, 5H), 6.02 (br, 1H), 5.29-5.20 (m, 1H), 4.72 (d, 2H),4.66-4.54 (m, 2H), 3.72 (br, 2H), 2.18-2.06 (m, 2H), 2.06-1.91 (m, 2H),1.97 (s, 3H), 1.54 (d, 6H), 1.36-1.15 (m, 4H); API MS m/z=500[C₂₃H₃₀BrN₇O+H]⁺.

Example 49 Preparation of Compound 64

[1420] Compound 61 (0.05 g, 0.11 mmol) was dissolved in CH₂Cl₂ (3 mL)and Et₃N (2 mL) and placed in an ice bath for 10 min. Compound 63 (0.06g, 0.22 mmol) was dissolved in CH₂Cl₂ (2 mL), added dropwise, and rinsedwith CH₂Cl₂ (1.5 mL). The ice bath was removed after 20 min and thereaction was allowed to stir for 7 d. The reaction mixture was dilutedwith CH₂Cl₂, washed with 2N HCl until the aqueous layer was acidic,washed with NaHCO₃, dried over MgSO₄, and evaporated. The desiredproduct was isolated by column chromatography and dried in vacuo toyield 64 (0.04 g, 50%) as a green solid: ¹H NMR (300 MHz, CDCl₃) δ 8.53(d, 1H), 8.32-8.20 (m, 2H), 7.59-7.35 (m, 4H), 7.23-7.11 (m, 4H), 6.02(br, 1H), 4.69-4.45 (m, 5H), 3.57 (br, 1H), 3.12 (br, 1H), 2.87 (s, 1H),1.97 (br, 2H), 1.75 (br, 2H), 1.48 (d, 6H), 1.27-0.97 (m, 4H); API MSm/z=693 [C₃₃H₃₉BrN₈O₂S+H]⁺.

Example 50 Preparation of Compound 65

[1421] Compound 61 (0.05 g, 0.11 mmol) was dissolved in CH₂Cl₂ (3 mL)and Et₃N (2 mL) and placed in an MeOH/ice bath. Methanesulfonyl chloride(0.012 mg, 0.11 mmol) in CH₂Cl₂ (2.3 mL) was slowly added. The reactionmixture and ice bath was allowed to come to room temperature. After 1.5h, the reaction mixture was diluted with CH₂Cl₂, washed with 2N HCluntil the aqueous layer was acidic. The organic layer was washed withNaHCO₃, dried over MgSO₄, filtered, and evaporated. The product waspurified by column chromatography, and dried in vacuo for 14 h to yield65 (13 mg, 24%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ7.50-7.17 (m, 5H), 5.90 (br, 1H), 4.75-4.57 (m, 3H), 4.11 (d, 1H), 3.69(br, 1H), 3.30 (br, 1H), 2.99 (s, 3H), 2.18-2.03 (m, 4H), 1.69 (d, 6H),1.42-1.15 (m, 5H); API MS m/z=538 [C₂₂H₃₀BrN₇O₂S+H]⁺.

Example 51 Preparation of Compound 66

[1422] Compound 61 (0.05 g, 0.11 mmol) was dissolved in toluene (4 mL).2-Acetylphenylisocyanate (0.024 g, 0.15 mmol) diluted with toluene (1mL) and added to compound 61. Toluene (6 mL) was added to the reactionmixture. The reaction mixture was placed under reflux for 19 h. Theproduct was purified by column chromatography, concentrated, and driedin vacuo for 23 h to yield 66 (42 mg, 62%) as an off-white solid: ¹H NMR(300 MHz, CDCl₃) δ 7.87-7.20 (m, 9H), 6.41 (s, 1H), 5.86 (br, 1H),4.75-4.54 (m, 4H), 3.69 (br, 1H), 2.60 (s, 3H), 2.12 (br, 4H), 1.51 (d,6H), 1.42-1.15 (m, 5H); API MS m/z=619 [C₃₀H₃₅BrN₈O₂+H]⁺.

Example 52 Preparation of Compound 67

[1423] Compound 61 (0.04 g, 0.10 mmol) was dissolved in CH₂Cl₂ (2 mL)and pyridine (0.5 mL). Cyclopropanecarbonyl chloride (0.05 g, 0.44 mmol)was added along with DMAP (small amount). The reaction mixture wasallowed to stir at room temperature for 2.25 h. The reaction mixture wasdiluted with CH₂Cl₂, washed with 2N HCl, saturated NaHCO₃, dried overMgSO₄, filtered, and evaporated. The product was isolated by columnchromatography to yield 67 (0.03 g, 63%) as a white solid: ¹H NMR (300MHz, CDCl₃) δ 7.50-7.20 (m, 5H), 5.96 (br, 1H), 5.41 (d, 1H), 4.72 (d,2H), 4.66-4.54 (m, 2H), 3.72 (br, 2H), 2.18-1.97 (m, 4H), 1.51 (d, 6H),1.36-1.15 (m, 5H), 1.06-0.88 (m, 2H), 0.79-0.67 (m, 2H); API MS m/z=526[C₂₅H₃₂BrN₇O+H]⁺.

Example 53 Preparation of Compound 69

[1424] To a solution of 4-biphenylcarboxaldehyde (1.0 g, 5.49 mmol) inMeOH (20 mL) was added NaBH₃CN (0.69 g, 11.0 mmol), and NH₄OH (15 mL)and the mixture was stirred at room temperature overnight. To this addedHCl and extracted with CHCl₃. The resulting aqueous layer was brought topH>7 with sodium bicarbonate and then extracted with CHCl₃. The solutionwas dried with MgSO₄, filtered, and evaporated to give 69 (200 mg) as awhite solid: EI MS m/z=183 [C₁₃H₁₃N]⁺.

Example 54 Preparation of Compound 69

[1425] To compound 70 (2.75 g, 13.9 mmol) was added anhydrous THF (60mL), heated to reflux, and kept under nitrogen. IM Borane-THF (69.7 mL)was added dropwise to 70 through an addition funnel resulting in ahomogeneous solution. The solution was refluxed for 18 h. The reactionmixture was cooled in an ice water bath and quenched with H₂O, 2N HCl(20 mL), followed by 3N NaOH (60 mL). The reaction mixture was extractedwith EtOAc (3×). The organic extracts were washed with brine, and driedover sodium sulfate. The crude product was concentrated, dissolved inMeOH, and HCl gas was bubbled through the solution. The solution wasfiltered in vacuo to give 69 as a white solid: ¹H NMR (300 MHz, CD₃OD) δ7.71 (d, 2H), 7.63 (d, 2H), 7.52 (d, 2H), 7.47-7.30 (m, 3H), 4.13 (s,2H).

Example 55 Preparation of Compound 71

[1426] To compound 1 (6.8 g, 36.0 mmol) and 69 (8.0 g, 36.5 mmol) wasadded H₂O (60 mL) and Hünigs base (9.0 g, 70.0 mmol). The mixture wasstirred and heated to reflux for 5 h during which time H₂O (50 mL) wasadded as the reaction continued to thicken. The crude product wascollected by filtration, washed with H₂O (500 mL) and EtOH (2×30 mL),air dried, and dried in vacuo to give 71 (11.1 g, 92%): mp 267-269° C.

Example 56 Preparation of Compound 72

[1427] Compound 71 (4.7 g, 14.0 mmol), K₂CO₃ (15.0 g, 109 mmol), DMSO(80 mL), and 2-iodopropane (9.4 g, 55.0 mmol) were combined and stirredovernight. H₂O and EtOAc were added. The EtOAc layer was separated andwashed with brine (3×). The EtOAc solution was dried with MgSO₄,concentrated, and crystallized from EtOAc to give 72 (3.5 g, 66%): mp139-140° C.

Example 57 Preparation of Compound 73

[1428] Compound 72 (2.00 g, 5.30 mmol) and (R)-(−)-2-amino-1-butanol(10.8 g, 121 mmol) were combined in a sealed tube, and heated in an oilbath at 190° C. for 2 h. The solution was cooled to 60° C., diluted inEtOAc, washed with brine (4×), dried with Na₂SO₄, and concentrated.Purification by column chromatography on SiO₂ gave the desired product73 (1.72 g, 75%) as a foam: ¹H NMR (300 MHz, CDCl₃) δ 7.65-7.10 (m, 9H),6.40-6.10 (bs, 1H), 5.05-4.85 (m, 1H), 4.85-4.67 (m, 1H), 4.60(heptuplet, 1H), 4.00-3.70 (dd, 2H), 3.76-3.50 (m, 1H), 1.95 (bs, 1H),1.80-1.55 (m, 2H), 1.51 (d, 6H), 1.03 (t, 3H); IR (CH₂Cl₂) 3301, 2969,1601, 1488, 1389, 1255, 762, 698 cm⁻¹; API MS m/z=431 [C₂₅H₃₀N₆O+H]⁺.

Example 58 Preparation of Compound 74

[1429] Compound 72 (0.23 g, 0.60 mmol), cis-1,2-diaminocyclohexane (0.72mL, 6.0 mmol), and ethanol (2 mL) were combined in a sealed tube andheated in an oil bath at 155° C. for 5 d. The ethanol was removed invacuo and the crude reaction mixture was filtered through a silica plug.The reaction mixture was chromatographed on silica gel, the resultingorange solid was dissolved in CH₂Cl₂ and a portion of activated charcoalwas added. The solution was filtered through a pad of celite andconcentrated to give 74 as a yellow solid (0.04 g, 27%): ¹H NMR (300MHz, CDCl₃) 7.59-7.31 (m, 10H), 6.00 (s, 1H), 5.09 (d, 1H), 4.83 (s,2H), 4.68-4.62 (m, 1H), 4.11 (s, 1H), 3.70-3.65 (m, 2H), 3.18-3.16 (m,1H), 2.02 (s, 2H), 1.67-1.42 (m, 12H); CI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 59 Preparation of Compound 75

[1430] Compound 72 (0.17 g, 0.45 mmol), trans-1,4-diaminocyclohexane(0.53 g, 4.69 mmol), and EtOH (5 mL) were combined in a sealed tube andheated at 155° C. for 5 d. The EtOH was removed in vacuo and the crudemixture was subjected to flash chromatography on silica gel.Recrystallization from CHCl₃/MeOH gave 75 (5.8 mg) as an off-whitecrystalline solid: mp 110-112° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.31(m, 10H), 5.95 (s, 1H), 4.88-4.78 (m, 2H), 4.69-4.60 (m, 2H), 3.88-3.78(m, 1H), 3.07-2.98 (m, 1H), 2.26-2.10 (m, 4H), 1.62-1.52 (m, 8H),1.29-1.15 (m, 4H); CI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 60 Preparation of Compound 76

[1431] Compound 75 (0.05 g, 0.11 mmol) was dissolved in CH₂Cl₂ and thesolution cooled to 0° C. under an argon atmosphere. A catalytic amountof DMAP, triethylamine (50 L, 0.36 mmol), followed by the acetylchloride (25 L, 0.36 mmol) were added to the reaction mixture. Thesolution was warmed to room temperature and washed with NaHCO₃ (5%),water, and brine. The solution was dried over Na₂SO₄ and concentrated.Purification by flash chromatography on silica gel gave 76 (0.028 g,53%) as a pale yellow solid: mp 224-225° C.; ¹H NMR (300 MHz, CDCl₃) δ7.59-7.31 (m, 10H), 5.93 (s, 1H), 5.26 (d, 1H), 4.81 (s, 2H), 4.65-4.58(m, 1H), 3.78-3.75 (m, 2H), 2.18-1.99 (m, 4H), 1.95 (s, 3H), 1.77 (s,1H), 1.53 (d, 6H), 1.32-1.22 (m, 4H); CI MS m/z=498 [C₂₉H₃₅N₇O+H]⁺.

Example 61 Preparation of Compound 77

[1432] Compound 72 (0.15 g, 0.40 mmol), trans-4-aminocyclohexanolhydrochloride (0.31 g, 1.99 mmol), Et₃N (0.11 mL, 0.8 mmol), and EtOH (5mL) were combined and heated in a sealed tube at 155° C. for 4 d.Additional trans-4-aminocyclohexanol hydrochloride (0.34 g, 2.2 mmol)and triethylamine (0.60 mL, 4.3 mmol) were added and the heat wasresumed at 155° C. overnight. The crude product was purified by flashcolumn chromatography to give 77 (0.036 g, 20%) as an off-white solid:mp 196-200° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.30 (m, 10H), 5.97 (s,1H), 4.83-4.81 (m, 2H), 4.66-4.60 (m, 2H), 3.82-3.77 (m, 1H), 3.69-3.62(m, 1H), 2.17-2.13 (m, 2H), 2.01-1.97 (m, 2H), 1.68 (s, 1H), 1.53 (d,6H), 1.49-1.20 (m, 4H); CI MS m/z=457 [C₂₇H₃₃N₆O+H]⁺.

Example 62 Preparation of Compound 78

[1433] To compound 61 (0.12 g, 0.26 mmol), was added compound 16 (0.12g, 0.33 mmol), and Pd(PPh₃)₄ (0.06 g, 0.056 mmol) and toluene (5 mL).The resulting mixture was degassed for 10 min with argon. The mixturewas heated at 140° C. for 3 h. The cooled solution was diluted withsaturated NaHCO₃ and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated to give a pale yellow oil which crystallized uponstanding at room temperature. The crude product was purified by columnchromatography and concentrated to give a white solid. The solid wasprecipitated with acetonitrile, filtered, washed with ether and hexaneto give 78 (0.02 g, 18%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (d, 1H), 8.01(d, 1H), 7.93-7.83 (m, 2H), 7.59-7.44 (m, 4H), 7.34-7.29 (m, 1H), 6.25(s, 1H), 4.70-4.60 (m, 2H), 4.57-4.49 (m, 2H), 3.65-3.52 (m, 1H),2.98-2.88 (m, 1H), 1.98-1.90 (m, 4H), 1.48 (d, 6H), 1.42-1.18 (m, 6H);CI MS m/z=457 [C₂₆H₃₂N₈+H]⁺.

Example 63 Preparation of Compound 78

[1434] To compound 24 (200 mg, 0.53 mmol) was addedtrans-1,4-diaminocyclohexane (2.00 g, 17 mmol) and EtOH (4 mL). Thereagents were heated in a sealed tube in an oil bath at 170° C. for 18h. The mixture was cooled to 60° C. and partitioned between EtOAc andbrine. The EtOAc layer was separated, washed with brine (3×), dried withNa₂SO₄, and concentrated to give 78 (0.12 g, 50%): mp 135-138° C.; ¹HNMR (300 MHz, CDCl₃) δ 8.03-7.82 (m, 2H), 7.80-7.58 (m, 3H), 7.57-7.30(m, 3H), 7.30-7.05 (m, 1H), 6.20 (bs, 1H), 5.95-4.73 (m, 2H), 4.73-4.45(m, 2H), 3.90-3.60 (m, 1H), 2.80-2.52 (m, 1H), 2.25-1.80 (m, 4H),1.80-1.60 (bs, 3H), 1.52 (d, 6H), 1.38-1.05 (m, 4H); IR (KBr) 3422,2927, 1599, 1489, 1253, 779 cm⁻¹; API MS m/z=457 [C₂₆H₃₂N₈+H]⁺.

Example 64 Preparation of Compound 79

[1435] Compound 78 (50 mg, 0.11 mmol) was dissolved in CH₂Cl₂ (2 mL) andstirred at room temperature. Pyridine (0.5 mL), Ac₂O (0.5 mL, 4.9 mmol),and DMAP (few crystals) were added to the reaction mixture and stirredfor 2 h. The solution was diluted in CH₂Cl₂ and washed in 2N HCl. TheHCl layer was concentrated, CH₂Cl₂ was added and the aqueous phaseneutralized with saturated NaHCO₃. The CH₂Cl₂ layer was separated, dried(MgSO₄), and concentrated to give 79 (0.03 g, 55%) as a white solid: ¹HNMR (300 MHz, CDCl₃) δ 8.00-7.80 (m, 2H), 7.81-7.57 (m, 2H), 7.56-7.33(m, 3H), 7.30-7.05 (m, 2H), 6.15-5.90 (bs, 1H), 5.47-5.28 (m, 1H),4.96-4.72 (m, 2H), 4.73-4.45 (m, 2H), 2.25-1.82 (m, 4H), 2.00 (s, 3H),1.54 (d, 6H), 1.40-1.00 (m, 4H); API MS m/z=499 [C₂₈H₃₄N₈O+H]⁺.

Example 65 Preparation of Compound 80

[1436] Compound 74 (0.02 g, 0.05 mmol) was dissolved in dry benzene (5mL) and stirred under a blanket of argon. The solution was cooled in anice bath and phenylisocyanate (25 L, 0.23 mmol) was added dropwise. Theice bath was removed and the mixture stirred at room temperature for 0.5h. The solvent was evaporated in vacuo to give a yellow oil. The crudeproduct was purified by flash column chromatography on silica gel togive 80 (0.008 g): ¹H NMR (300 MHz, CDCl₃) δ 7.53-7.30 (m, 10H),7.13-7.06 (m, 4H), 6.98-6.88 (m, 1H), 6.62 (s, 1H), 6.02 (s, 1H), 5.65(s, 1H), 5.02 (d, 1H), 4.85-4.70 (m, 2H), 4.60-4.52 (m, 1H), 4.45-4.40(m, 1H), 4.36-4.22 (m, 2H), 4.00 (s, 1H), 1.91-1.60 (m, 6H), 1.48-1.43(m, 6H).

Example 66 Preparation of Compound 82

[1437] A mixture of 6-chloronicotinamide (2.96 g, 18.9 mmol),phenylboronic acid (2.54 g, 20.8 mmol), and Pd(PPh₃)₄ (643 mg, 0.565mmol) in toluene (47 mL), ethanol (7 mL) and 2M aqueous sodium carbonatesolution (21 mL, 43 mmol) was stirred and heated at 90-100° C. undernitrogen for 16 h. The mixture was cooled to room temperature andfiltered. The resulting solid was washed with water (2×20 mL) and driedin vacuo. To the dried solid was added methanol (50 mL). The mixture wasstirred at reflux, cooled to room temperature, and filtered to give theproduct (90%) as a powder: mp 218-220° C.; ¹H NMR (500 Hz, DMSO-d₆) δ9.23 (d, J=2.5 Hz, 1H), 8.41 (dd, J₁=2.2 Hz, J₂=8.3 Hz, 1H), 8.32 (s,1H), 8.27 (d, J=7.1 Hz, 2H), 8.20 (d, J=8.5 Hz, 1H), 7.74 (s, 1H),7.66-7.60 (m, 3H).

Example 67 Preparation of Compound 83

[1438] To NaBH₄ (0.19 g, 5 mmol) in 1,4-dioxane (4 mL) was added HOAc(0.3 g, 5 mmol) in 1,4-dioxane (2 mL) slowly while the flask was cooledwith ice. 5 Compound 82 (0.2 g, 1 mmol) was then added. The mixture wasstirred at reflux at 100-110° C. for 4 h and the solvent was evaporated.To this mixture was added water (2 mL) slowly. The mixture was extractedwith CH₂Cl₂ (4×10 mL), washed with water (3×5 mL), dried with anhydroussodium sulfate, concentrated, and purified by flash chromatography onsilica gel to provide the product as a yellow liquid. This wastriturated with ethanol (1 mL) to provide a white solid which wascollected (60%) and dried: mp 97-99° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.60(d, J=2 Hz, 1H), 7.97-7.95 (m, 2H), 7.72-7.67 (m, 2H), 7.47-7.37 (m,3H), 3.90 (s, 2H), 1.77 (bs, 2H).

Example 68 Preparation of Compound 84

[1439] A mixture of 2,6-dichloropurine (1, 0.19 g, 1 mmol), amine 83(0.39 g, 2.15 mmol) in ethanol (1 3 mL), and water (3 mL) was heated at100-110° C. under nitrogen for 24 h and then cooled to room temperature.The mixture was concentrated and water (5 mL) was added. A solid wasfiltered and washed with water (2×5 mL) and dried under vacuum to givethe product (80%) as a yellow solid: mp 260° C. (dec); ¹H NMR (500 Hz,DMSO-d₆) δ 13.26 (s, 1H), 8.79 (s, 1H), 8.27 (s, 1H), 8.16 (d, J=7.1 Hz,2H), 8.34 (d, J=7.3 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.63-7.52 (m, 3H),4.81 (s, 2H).

Example 69 Preparation of Compound 85

[1440] To a solution of compound 84 (0.34 g, 1 mmol) in DMSO (5 mL), wasadded potassium carbonate (0.7 g, 5 mmol) and 2-iodopropane (0.5 g, 3mmol). The mixture was stirred at ambient temperature under nitrogen for24 h and poured into ice water (30 mL). After filtration, the solid waswashed with water (4×5 mL), dried under vacuum to give the crude productas a yellow solid. Flash column chromatography of the crude product onsilica gel and recrystallization provided the pure product (63%) asivory colored crystals: mp 138-139° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.70(d, J=1.5 Hz, 1H), 7.97 (m, 2H), 7.79 (dd, J₁=1.7 Hz, J₂=8.1 Hz, 1H),7.71 (s, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.48-7.39 (m, 3H), 4.87 (s, 2H),4.80 (m, 1H), 1.55 (d, J=6.8 Hz, 6H); CI MS m/z=379 [C₂₀H₁₉ClN₆+H]⁺.Anal. Calcd. for C₂₀H₁₉ClN₆: C, 63.41; H, 5.05; N, 22.18. Found: C,63.75; H, 5.09; N, 21.87.

Example 70 Preparation of Compound 86

[1441] To compound 85 (0.1 g, 0.26 mmol) was addedtrans-1,4-diaminocyclohexane (1 g, 8.8 mmol) and EtOH (2 mL). Thereaction mixture was heated in a sealed tube in an oil bath at 120° C.The crude product was purified by column chromatography to give 86 (0.08g, 67%): ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, 1H), 7.83-7.97 (m, 2H),7.70-7.83 (m, 1H), 7.55-7.73 (m, 1H), 7.30-7.55 (m, 4H), 6.35 (bs, 1H),4.72-4.95 (m, 2H), 4.50-4.72 (m, 2H), 3.63-3.85 (m, 1H), 2.65-2.90 (m,1H), 2.37-2.63 (bs, 2H), 1.80-2.20 (dd, 4H), 1.53 (d, 6H), 0.72-1.42 (m,4H); API MS m/z=457 [C₂₆H₂₂N₈+H]⁺.

Example 71 Preparation of Compound 87

[1442] Compound 86 (0.08 g, 0.18 mmol) was stirred at room temperaturein CH₂Cl₂ (3 mL). Pyridine (100 mg, 0.82 mmol) was added followed byAc₂O (100 mg, 0.98 mmol) and DMAP (few crystals). After 2 h, more CH₂Cl₂(3 mL) was added and the mixture was washed carefully with 2N HCl (10drops), and saturated NaHCO₃. After separation of the CH₂Cl₂ layer, theorganic phase was then dried with Na₂SO₄ and concentrated to give 87 (80mg, 92%): ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 8.30-7.03 (m, 9H),5.75-5.38 (m, 1H), 5.02 (bs, 1H), 4.83 (bs, 2H), 4.72-4.40 (m, 1H), 3.73(bs, 2H), 2.52-1.83 (m, 4H), 1.98 (s, 3H), 1.52 (d, 6H), 1.50-1.00 (m,4H); API MS m/z=499 [C₂₈H₃₄N₈O+H]⁺.

Example 72 Preparation of Compound 88

[1443] Compound 85 (0.05 g, 0.13 mmol) and (R)-(−)-2-amino-1-butanol(0.50 g, 5.6 mmol) were combined in a sealed tube and heated in an oilbath at 190° C. for 2 h then cooled to room temperature. The mixture waspartitioned between EtOAc and brine, washed with brine (3×), dried withNa₂SO₄, and concentrated. The mixture was allowed to stand over theweekend and then purified by column chromatography on SiO₂ to give 88(0.01 g, 17%) as a foam: ¹H NMR (300 MHz, CDCl₃) δ 8.70 (s, 1H),8.05-7.82 (m, 2H), 7.82-7.55 (m, 2H), 7.57-7.30 (m, 4H), 6.55 (bs, 1H),5.00-4.88 (s, 1H), 4.78 (s, 2H), 4.60 (heptuplet, 1H), 3.98-3.83 (m,1H), 3.84-3.70 (m, 1H), 3.70-3.50 (m, 1H), 2.90 (bs, 1H), 1.75-1.55 (m,2H), 1.53 (d, 6H), 1.00 (t, 3H); API MS m/z=432 [C₂₄H₂₉N₇O+H]⁺.

Example 73 Preparation of Compound 89

[1444] A mixture of 6-chloronicotinamide (2.5 g, 16 mmol), crude2-trimethylstannylpyridine (5.8 g, 24 mmol), and PdCl₂(PPh₃)₂ (560 mg,0.8 mmol) in DMF (35 mL) was heated at 150-160° C. in a pressure tubefor 17 h. The DMF was distilled off under reduced pressure and theresidue was extracted with ethyl acetate (6×30 mL) and concentrated. Theresidue was treated with methanol (15 mL) and a solid separated whichwas filtered and dried to give the product (40%) as a powder: mp237-240° C.; ¹H NMR (500 Hz, DMSO-d₆) 9.22 (d, J=2.2 Hz, 1H), 8.83 (m,1H) 8.57-8.53 (m, 2H), 8.48-8.46 (m, 1H), 8.38 (s, 1H), 8.11-8.07 (m,1H), 7.78 (s, 1H), 7.63-7.60 (m, 1H).

Example 74 Preparation of Compound 90

[1445] To NaBH₄ (0.2 g, 5 mmol) in 1,4-dioxane (4 mL) was added HOAc(0.29 g, 5 mmol) in 1,4-dioxane (2 mL) slowly while the flask was cooledwith ice. Compound 89 (0.199 g, 1 mmol) was then added. The mixture wasstirred at reflux at 100-110° C. for 4 h and the solvent was evaporated.To this mixture was added water (2 mL) slowly. The mixture was extractedwith CH₂Cl₂ (4×10 mL), washed with water (3×5 mL), dried with anhydroussodium sulfate, filtered, concentrated, and purified by flashchromatography on silica gel to provide the product as a yellow liquid.This was triturated with ethanol (1 mL) and a white solid (32%) wascollected and dried: mp 109-112° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.63 (m,1H), 8.58 (s, 1H), 8.32 (m, 2H), 7.77 (m, 2H), 7.25 (m, 1H), 3.91 (s,2H), 1.94 (s, 2H).

Example 75 Preparation of Compound 91

[1446] A mixture of 2,6-dichloropurine (1, 0.2 g, 1 mmol), compound 90(0.4 g, 2.2 mmol) in ethanol (13 mL), and water (3 mL) was heated at100-110° C. under nitrogen for 24 h and then cooled to room temperature.The mixture was concentrated and water (5 mL) was added. A solid wasfiltered and washed with water (2×5 mL) and dried under vacuum to givethe product (83%) as a yellow solid: mp 248° C. (dec); ¹H NMR (500 Hz,DMSO-d₆) δ 13.27 (s, 1H), 8.81 (s, 1H), 8.78 (d, J=4.1 Hz, 1H), 8.47 (m,2H), 8.28 (s, 1H), 8.06-8.01 (m, 2H), 7.50 (m, 1H), 4.84 (s, 2H).

Example 76 Preparation of Compound 92

[1447] To the solution of compound 91 (0.35 g, 1 mmol) in DMSO (5 mL),added potassium carbonate (0.68 g, 5 mmol) and 2-iodopropane (0.49 g, 3mmol). The mixture was stirred at ambient temperature under nitrogen for24 h and poured into ice water (30 mL). After filtration, the solid waswashed with water (4×5 mL), dried under vacuum to give the crude productas a yellow solid. Flash column chromatography of the crude product onsilica gel and recrystallization provided the pure product (64%) aswhite crystals: mp 150-151° C.; ¹H NMR (500 Hz, CDCl₃) δ 8.71 (d, J=1.9Hz, 1H), 8.67 (m, 1H), 8.38-8.36 (m, 2H), 7.86-7.79 (m, 2H), 7.75 (s,1H), 7.30 (m, 1H), 4.91 (s, 2H), 4.82 (m, 1H), 1.57 (d, J=6.8 Hz, 6H);CI MS m/z=380 [C₁₉H₁₈ClN₇+H]⁺. Anal. Calcd. for C₁₉H₁₈ClN₇: C, 60.08; H,4.78; N, 25.81. Found: C, 59.76; H, 4.72; N, 25.57.

Example 77 Preparation of Compound 93

[1448] Compound 92 (150 mg, 0.39 mmol), trans-1,4-diaminocyclohexane(1.50 g, 13.1 mmol), and EtOH (30 mL) were heated to 120° C. for 26 h ina sealed tube. The mixture was cooled, additional EtOAc was added,washed with brine, dried over Na₂SO₄, and concentrated to give 93 (170mg, 94%) as a waxy solid: ¹H NMR (300 MHz, CDCl₃) δ 8.77-8.60 (m, 1H),8.44-8.27 (m, 2H), 7.90-7.75 (m, 2H), 7.50 (s, 1H), 7.36-7.22 (m, 2H),6.27 (bs, 1H), 4.96-4.73 (m, 2H), 4.73-4.52 (m, 2H), 3.84-3.60 (m, 1H),2.80-2.57 (m, 1H), 2.22-2.00 (m, 2H), 2.00-1.67 (m, 5H), 1.54 (d, 6H),1.38-1.05 (m, 4H); API MS m/z=458 [C₂₅H₃₁N₉+H]⁺.

Example 78 Preparation of Compound 94

[1449] Compound 93 (0.15 g, 0.33 mmol) was dissolved in CH₂Cl₂ (6 mL)and then pyridine (0.200 g, 1.64 mmol) followed by Ac₂O (0.200 g, 1.96mmol) and DMAP (few crystals) were added. The reaction mixture wasstirred for 2 h, washed with 2N HCl and NaHCO₃, extracted with CH₂Cl₂,dried with Na₂SO₄, and concentrated to give 94 (0.17 g, 69%) as a solid:mp 141-145° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.80-8.63 (m, 1H), 8.45-8.25(t, 2H), 7.95-7.73 (m, 1H), 7.52 (s, 1H), 7.35-7.20 (m, 2H), 6.20 (bs,1H), 5.50-5.30 (m, 1H), 4.98-4.75 (m, 2H), 4.75-4.50 (m, 2H), 3.84-3.60(m, 2H), 2.27-1.87 (m, 4H), 2.00 (s, 3H), 1.52 (d, 6H), 1.40-1.10 (m,4H); API MS m/z=499 [C₂₇H₃₃N₉O+H]⁺.

Example 79 Preparation of Compound 95

[1450] DME (3 mL), tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01mmol), and PPh₃ (0.04 g, 0.15 mmol) were added to a round bottomed flaskequipped with a condensor and maintained under an argon atmosphere. Tothe solution was added compound 11 (0.13 g, 0.25 mmol). 3-Fluorobenzeneboronic acid (0.123 g, 0.9 mmol) was dissolved in a solution of 2MNa₂CO₃ (0.6 mL) and DME (1 mL), and added to the reaction mixture. Themixture was stirred under argon and refluxed for 19 h then stirred atroom temperature for 22 h. The reaction mixture was diluted with H₂O,extracted with CH₂Cl₂, washed with brine. The organic layer was driedover Na₂SO₄ and evaporated. The reaction mixture was purified twice bycolumn chromatography and dried under high vacuum to give a white solid(17 mg, 14%): ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.32 (m, 8H), 7.08-6.99 (m,1H), 5.86 (br, 1H), 4.83 (d, 2H), 4.71-4.56 (m, 1H), 3.77 (br, 2H), 2.70(br, 1H), 2.12 (d, 1H), 1.88 (d, 1H), 1.51 (d, 6H), 1.22 (d, 5H),0.94-0.70 (m, 3H); API MS m/z=474 [C₂₇H₃₂FN₇+H]⁺.

Example 80 Preparation of Compound 96

[1451] A stock solution of acetic anhydride was made by mixing CH₂Cl₂(16 mL), pyridine (4 mL), and Ac₂O (0.16 mL). To this stock solution(1.5 mL) was added compound 95 (0.01 g, 0.02 mmol) followed by DMAP (fewcrystals). The reaction mixture was allowed to stir at room temperaturefor 26 h. The reaction mixture was then diluted with CH₂Cl₂, washed with2N HCl until the aqueous layer was acidic, washed with NaHCO₃, driedover MgSO₄, evaporated, and dried in vacuo for 15 h to give a whitesolid (11 mg, 92%): ¹H NMR (300 MHz, CDCl₃) δ 8.65 (br, 1H), 7.77-7.17(m, 8H), 7.11-6.99 (m, 1H), 5.14 (br, 2H), 4.90 (br, 1H), 4.69 (br, 1H),3.78 (br, 2H), 2.09 (br, 3H), 1.94 (s, 2H), 1.57 (d, 6H), 1.42 (br, 4H),1.24 (s, 2H), 0.94-0.76 (m, 1H); CI MS m/z=516 [C₂₉H₃₄FN₇O+H]⁺.

Example 81 Preparation of Compound 97

[1452] A stock solution of acetic anhydride was made by mixing CH₂Cl₂(16 mL), pyridine (4 mL), and Ac₂O (0.16 mL). To this stock solution(1.5 mL) was added compound 13 (0.01 g, 0.02 mmol) followed by DMAP (fewcrystals). The reaction mixture was allowed to stir at room temperaturefor 2 h. The reaction mixture was then diluted with CH₂Cl₂, washed with2N HCl until it was acidic, washed with NaHCO₃, dried over MgSO₄, andevaporated to give a white solid (8 mg, 89%): ¹H NMR (300 MHz, CDCl₃) δ8.78 (d, 1H), 8.44 (t, 1H), 7.95 (t, 2H), 7.69-7.45 (m, 5H), 5.30 (br,2H), 4.84 (br, 1H), 4.68 (br, 1H), 3.78 (br, 2H), 2.39 (s, 3H), 2.10(br, 4H), 1.96 (s, 2H), 1.57 (br, 10H), 1.25 (s, 2H), 0.88 (br, 1H); APIMS m/z=512 [C₃₀H₃₇N₇O+H]⁺.

Example 82 Preparation of Compound 98

[1453] DME (3 mL), tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01mmol), and PPh₃ (0.04 g, 0.15 mmol) were added to a round bottom flaskequipped with condensor and maintained under an argon atmosphere. Iodide11 (0.13 g, 0.26 mmol), and 3-chlorobenzene boronic acid (0.15 g, 0.93mmol) was dissolved in 2M Na₂CO₃ (0.6 mL) and DME (1 mL). This was thenadded to the reaction mixture and refluxed for 19.5 h then stirred atroom temperature for 30 h. The reaction mixture was then diluted withH₂O, extracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄,filtered, and evaporated. The reaction mixture was purified by columnchromatography (3×) and evaporated. The product was triturated inhexanes, filtered, and dried in vacuo for 1 h to give a white solid (16mg): ¹H NMR (300 MHz, CDCl₃) δ 7.56-7.38 (m, 9H), 6.01 (br, 1H), 4.80(d, 2H), 4.71-4.62 (m, 1H), 3.77 (br, 2H), 2.73 (br, 1H), 2.19-2.04 (m,1H), 1.94-1.85 (m, 1H), 1.51 (d, 6H), 1.24 (d, 5H), 0.91-1.76 (m, 3H);API MS m/z=490 [C₂₇H₃₂ClN₇+H]⁺.

Example 83 Preparation of Compound 99

[1454] A stock solution of acetic anhydride was made by mixing CH₂Cl₂(16 mL), pyridine (4 mL), and Ac₂O (0.16 mL). To this solution (1.5 mL)was added compound 98 (0.01 g, 0.02 mmol), followed by DMAP (fewcrystals). The reaction mixture was allowed to stir at room temperaturefor 2 h. The reaction mixture was diluted with CH₂Cl₂, washed with 2NHCl until the aqueous layer was acidic, washed with NaHCO₃, dried overMgSO₄, filtered, and evaporated to give a white solid (0.01 g, 83%): ¹HNMR (300 MHz, CDCl₃) δ 7.65-7.35 (m, 8H), 7.26-7.14 (m, 1H), 5.23 (br,1H), 4.66 (br, 1H), 3.78 (br, 2H), 2.18-2.00 (m, 4H), 1.94 (s, 3H), 1.54(d, 6H), 1.24 (s, 5H), 0.94-0.69 (m, 3H); API MS m/z=532[C₂₉H₃₄ClN₇O+H]⁺.

Example 84 Preparation of Compound 100

[1455] A stock solution of acetic anhydride was made by mixing CH₂Cl₂(16 mL), pyridine (4 mL), and Ac₂O (0.16 mL). To compound 14 (0.02 g,0.03 mmol) was added this solution (2 mL), followed by DMAP (fewcrystals). The reaction mixture was allowed to stir at room temperaturefor 3 h. The reaction mixture was diluted with CH₂Cl₂, washed with 2NHCl until the aqueous layer was acidic, washed with NaHCO₃, filtered,and evaporated to give a white solid (8 mg, 44%): ¹H NMR (300 MHz,CDCl₃) δ 7.41-7.32 (m, 7H), 7.26-7.14 (m, 1H), 5.96 (br, 1H), 5.23 (d,1H), 4.84 (br, 2H), 4.69-4.54 (m, 1H), 3.75 (br, 1H), 2.21-2.12 (m, 1H),2.09-1.96 (m, 1H), 1.97 (s, 3H), 1.54 (d, 6H), 1.36-1.15 (m, 5H), 0.85(br, 3H); API MS m/z=550 [C₂₉H₃₃ClFNγ O+H]⁺.

Example 85 Preparation of Compound 101

[1456] DME (3 mL), tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01mmol), and PPh₃ (0.04 g, 0.15 mmol) were added to a round bottomed flaskequipped with a condensor and maintained under an argon atmosphere.Compound 10 (0.13 g, 0.26 mmol) and 4-fluorobenzene boronic acid (0.13g, 0.95 mmol) was dissolved in 2M Na₂CO₃ (0.6 mL) and DME (1 mL). Thiswas then added to the reaction mixture and refluxed for 19 h thenstirred at room temperature for 72 h. The reaction mixture was thendiluted with H₂O, extracted with CH₂Cl₂, washed with brine, dried overNa₂SO₄, filtered, and evaporated. The reaction mixture was purified bycolumn chromatography on silica gel to give a white solid (17 mg, 14%):¹H NMR (300 MHz, CDCl₃) δ 7.56-7.38 (m, 8H), 7.11 (t, 1H), 5.81 (br,1H), 4.81 (d, 2H), 4.69-4.57 (m, 1H), 3.78 (br, 2H), 2.69 (br, 1H), 2.12(br, 1H), 1.88 (br, 1H), 1.54 (d, 6H), 1.33-1.12 (m, 5H), 0.85 (br, 3H);API MS m/z 474 [C₂₇H₃₂FN₇+H]⁺.

Example 86 Preparation of Compound 102

[1457] A stock solution of acetic anhydride was made by mixing CH₂Cl₂(16 mL), pyridine (4 mL), and Ac₂O (0.16 mL). To the solution (1.4 mL)was added compound 101 (0.01 g, 0.02 mmol), followed by DMAP (fewcrystals). The reaction mixture was allowed to stir at room temperaturefor 2.5 h. The reaction mixture was diluted with CH₂Cl₂, washed with 2NHCl until the aqueous layer was acidic, and washed with saturatedNaHCO₃. The organic layer was dried over MgSO₄ and evaporated to give aproduct (3 mg). The NaHCO₃ layer was further extracted with EtOAc (2×),the organic layers were combined, dried over MgSO₄, evaporated to giveproduct 102 (2 mg). The products were combined using EtOAc, evaporated,and dried in vacuo for 15 h to give product 102 (5 mg, 50%): ¹H NMR (300MHz, CDCl₃) δ 7.71-7.08 (m, 9H), 5.29 (br, 2H), 4.84 (br, 1H), 4.66 (br,1H), 3.78 (br, 2H), 2.09 (br, 4H), 1.97 (s, 1H), 1.57 (br, 3H), 1.24 (d,6H), 0.87 (br, 5H); API MS m/z=516 [C₂₉H₃₄FN₇O+H]⁺.

Example 87 Preparation of Compound 103

[1458] Compound 30 (0.10 g, 0.27 mmol) and trans-1,4-diaminocyclohexane(0.48 g, 4.2 mmol) were combined with EtOH (2 mL) in a sealed tube andheated at 190° C. for 24 h, and then stirred at room temperature for 46h. The reaction mixture was purified by column chromatography and driedin vacuo to give 103 as a white solid (0.10 g, 81%): ¹H NMR (300 MHz,CDCl₃) δ 8.83 (d, 1H), 8.58 (t, 1H), 7.87-7.83 (m, 1H), 7.55-7.47 (m,5H), 7.38-7.33 (m, 1H), 5.96 (br, 1H), 4.82 (d, 2H), 4.68-4.59 (m, 1H),3.75 (br, 2H), 2.69 (br, 1H), 2.14 (d, 2H), 1.86 (d, 2H), 1.54 (d, 6H),1.31-1.18 (m, 5H); API MS m/z=457 [C₂₆H₃₂N₈+H]⁺.

Example 88 Preparation of Compound 104

[1459] A stock solution of acetic anhydride was made by mixing CH₂Cl₂(16 mL), pyridine (4 mL), and Ac₂O (0.16 mL). To the solution (3.1 mL)was added compound 103 (0.02 g, 0.04 mmol), followed by DMAP (fewcrystals). The reaction mixture was allowed to stir at room temperaturefor 2.5 h. The reaction mixture was evaporated, dried in vacuo for 19 h,and purified by column chromatography to give a white solid (0.02 g): ¹HNMR (300 MHz, CDCl₃) δ 8.83 (d, 1H), 8.59 (t, 1H), 7.85 (d, 1H),7.55-7.47 (m, 5H), 7.38-7.34 (m, 1H), 5.89 (br, 1H), 5.25 (d, 2H), 4.85(br, 1H), 4.66-4.61 (m, 1H), 3.77 (br, 2H), 2.15 (br, 2H), 2.05 (br,2H), 1.97 (s, 2H), 1.54 (d, 6H), 1.33-1.25 (m, 5H), 0.88 (br, 1H); APIMS m/z=499 [C₂₈H₃₄N₈O+H]⁺.

Example 89 Preparation of Compound 106

[1460] Compound 72 (0.30 g, 0.80 mmol) and compound 105 (1.15 g, 6.50mmol) (Gardiner, J. M., et al. Tetrahedron, 42(11):515 (1995), which ishereby incorporated by reference, were combined with EtOH (7 mL) andallowed to reflux for 23 h. Triethylamine (1 mL) was added and thereaction was refluxed further for another 21 h. The reaction mixture wasthen transferred to a sealed tube and EtOH (3 mL) was added. Thereaction mixture was heated further at 100° C. for 3 h. The mixture waspurified by column chromatography to give 105 (0.13 g): ¹H NMR (300 MHz,CDCl₃) δ 7.57-7.26 (m, 10H) 5.58 (br, 1H), 5.10 (br, 1H), 4.83 (br, 1H),4.69-4.62 (m, 2H), 3.36-2.91 (m, 5H), 2.82-2.65 (m, 2H), 1.53 (d, 2H),1.44 (s, 9H), 1.25 (d, 1H), 1.13 (d, 3H); CI MS m/z=416[C₂₉H₃₉N₇O-Boc+H]⁺.

Example 90 Preparation of Compound 107

[1461] To compound 106 (0.10 g, 0.18 mmol) was added Et₂O (2 mL), CH₂Cl₂(1 mL) and MeOH (1 mL). During 16 h HCl/ether (1M, 5 mL) was added whilestirring. The resulting precipitate was collected by filtration anddried in vacuo for 30 min to provide 106 as an off-white solid (60 mg,81%): ¹H NMR (300 MHz, DMSO) δ 8.48 (br, 2H), 8.15 (br, 1H), 7.67-7.27(m, 10H), 4.79 (br, 1H), 3.60-3.42 (m, 3H), 3.18-3.06 (m, 2H), 3.03-2.91(m, 2H), 1.52 (d, 2H), 1.27 (d, 6H); CI MS m/z=416 [C₂₄H₂₉N₇+H]⁺.

Example 91 Preparation of Compound 108

[1462] A stock solution of acetic anhydride was made by mixing CH₂Cl₂(16 mL), pyridine (4 mL), and Ac₂O (0.16 mL). To this solution (5.6 mL)was added compound 107 (0.04 g, 0.09 mmol), followed by DMAP (fewcrystals). The reaction mixture was allowed to stir at room temperaturefor 2 h. The reaction mixture was diluted with CH₂Cl₂, washed with 2NHCl until acidic, the organic layer was washed with NaHCO₃, dried overMgSO₄, filtered, and evaporated to give a white solid (16 mg). Theproduct was purified by column chromatography to provide 108 as a white15 solid (0.01 g, 18%): ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.43 (m, 10H),6.60 (br, 1H), 5.91 (br, 1H), 5.04 (t, 1H), 4.84 (br, 2H), 4.72-4.59 (m,1H), 4.10-4.02 (m, 1H), 3.59-3.47 (m, 2H), 1.80 (s, 3H), 1.57 (d, 6H),1.19 (d, 3H); CI MS m/z=458 [C₂₆H₃₁N₇O+H]⁺.

Example 92 Preparation of Compound 109

[1463] Compound 61 (1.0 g, 2.18 mmol), 3-chlorophenylboronic acid (1.3g, 8.16 mmol), PPh₃ (0.3 g, 1.26 mmol), 2M Na₂CO₃ (5.0 mL), and DME (54mL) were added to a three-necked round-bottomed flask. The mixture wasdegassed with argon and heated to reflux for 40 min, cooled to roomtemperature, and then Pd₂(dba)₃ (0.08 g, 0.08 mmol) was added. Thereaction mixture was heated at reflux for 7 h. 3-Chlorophenylboronicacid (0.6 g) and Pd₂(dba)₃ (0.08 g) was then added and reflux continuedfor 12 h. The reaction mixture was cooled to room temperature, dilutedwith H₂O (50 mL), and extracted with CH₂Cl₂ (3×50 mL). The combinedorganic phases were washed with H₂O (50 mL), brine (50 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography and concentrated in vacuo to obtain compound109 (950 mg, 89%): mp 178-181° C.;

[1464]¹H NMR (500 MHz, CDCl₃) δ 7.56 (s, 1H), 7.42-7.54 (m, 6H),7.26-7.35 (m, 2H), 6.08 (bs, 1H), 4.81 (bs, 2H), 4.59-4.64 (m, 2H),3.75-3.81 (m, 1H), 2.65-2.72 (m, 1 H), 2.12 (d, 2H), 1.88 (d, 2H), 1.53(d, 6H), 1.18-1.27 (m, 4H); CI MS m/z=490 [C₂₇H₃₂ClN₇+H]⁺.

Example 93 Preparation of Compound 110

[1465] Compound 109 (500 mg, 1.02 mmol) was dissolved in anhydrousCH₂Cl₂ (30 mL), cooled with an ice-water bath, followed by the additionof DMAP (12.2 mg, 0.1 mmol), pyridine (124 μL, 1.53 mmol), and Ac₂O (106μL, 1.12 mmol). The reaction mixture was stirred for 30 min at 0° C. anice-water bath then stirred another 2 h at room temperature. Thereaction mixture was then concentrated in vacuo and the residue waspurified by column chromatography on silica gel. After removal of thesolvent, the residue was dried in vacuo to give 110 (339 mg, 63%): mp198-200° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.57 (s, 1H), 7.39-7.53 (m, 6H),7.27-7.37 (m, 2H), 6.31 (bs, 1H), 5.28 (d, 1H), 4.78 (bs, 2H), 4.70 (d,1H), 4.58-4.67 (m, 1H), 3.72-3.83 (m, 1H), 2.18 (d, 2H), 2.00 (d, 2H),1.90 (s, 3H), 1.51 (d, 6H), 1.18-1.31 (m, 4H); CI MS m/z=532[C₂₉H₃₄ClN₇O+H]⁺.

Example 94 Preparation of Compound 111

[1466] Compound 61 (1.0 g, 2.18 mmol), 2-thiopheneboronic acid (1.0 g,8.16 mmol), PPh₃ (0.3 g, 1.26 mmol), 2M Na₂CO₃ (5.0 mL), Pd₂(dba)₃ (0.08g, 0.08 mmol), and DME (54 mL) were added to a round-bottomed flask andpurged with argon. The reaction mixture was heated at reflux for 24 h.2-Thiopheneboronic acid (0.5 g), Pd₂(dba)₃ (0.1 g), and 2M Na₂CO₃ (2 mL)were added and heated to reflux for another 24 h. The reaction mixturewas cooled to room temperature, diluted with H₂O (50 mL) and extractedwith CH₂Cl₂ (3×50 mL). The organic phase was washed with H₂O (50 mL) andbrine (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo.The residue was repeatedly chromatographed on silica gel to obtain 111(574 mg, 59%): mp 109-110° C.; ¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, 2H),7.54 (s, 1H), 7.46 (d, 2H), 7.24-7.37 (m, 2H), 7.06 (t, 1H), 6.04 (bs,1H), 4.78 (bs, 2H), 4.59-4.69 (m, 2H), 3.75-3.81 (m, 1H), 2.67-2.74 (m,1H), 2.14 (d, 2H), 1.87 (d, 2H), 1.52 (d, 6H), 1.17-1.29 (m, 4H); CI MSm/z=462 [C₂₅H₃₁N₇S+H]⁺.

Example 95 Preparation of Compound 112

[1467] Compound 111 (410.0 mg, 0.89 mmol) was dissolved in anhydrousCH₂Cl₂ (30 mL) and purged with N₂ and cooled with an ice-water bath.Pyridine (108 mg, 1.34 mmol) and DMAP (10.9 mg, 0.09 mmol) followed byAc₂O (92 μL, 0.98 mmol) were added slowly. The reaction mixture wasstirred for 30 min in an ice-water bath followed by 2 h at roomtemperature. The reaction mixture was concentrated in vacuo. The residuewas chromatographed on silica gel to give 112 (325 mg, 73%): mp 237-244°C.; ¹H NMR (500 MHz, CDCl₃) δ 7.54 (d, 2H), 7.50 (s, 1H), 7.36 (d, 2H),7.24-7.37 (m, 2H), 7.08 (t, 1H), 6.06 (bs, 1H), 5.34 (s, 1H), 4.78 (bs,2H), 4.58-4.70 (m, 2H), 3.78 (bs, 2H), 2.17 (d, 2H), 2.04 (d, 2H), 1.96(s, 3H), 1.56 (d, 6H), 1.18-1.32 (m, 4H); CI MS m/z=504 [C₂₇H₃₃N₇OS+H]⁺.

Example 96 Preparation of Compound 113

[1468] Compound 12 (600 mg, 1.30 mmol) was dissolved in anhydrous CH₂Cl₂(40 mL), purged with N₂, and cooled to 0° C. followed by an addition ofDMAP (15.9 mg, 0.13 mmol), pyridine (165.3 mg, 1.95 mmol), and Ac₂O (135mg, 1.43 mmol). The mixture was stirred 30 min at 0° C. then 2 h at roomtemperature. The reaction mixture was concentrated in vacuo. The residuewas chromatographed on silica gel to give 113 (495 mg, 76%): mp 248-253°C.; ¹H NMR (500 MHz, CDCl₃) δ 7.54 (d, 2H), 7.46 (s, 1H), 7.35-7.41 (m,5H), 6.13 (bs, 1H), 5.28 (d, 1H), 4.78 (br, 2H), 4.61-4.63 (m, 2H), 3.75(bs, 2H), 2.14 (d, 2H), 1.97 (d, 2H), 1.95 (s, 3H), 1.52 (d, 6H),1.15-1.37 (m, 4H); CI MS m/z=504 [C₂₇H₃₃N₇OS+H]⁺.

Example 97 Preparation of Compound 114

[1469] To compound 61 (1.0 g, 2.18 mmol) was added PPh₃ (330 mg, 1.26mmol), 2M Na₂CO₃ (5 mL), DME (54 mL), and 4-carboxyphenylboronic acid(1.0 g, 6.03 mmol). The mixture was purged with N₂ for 45 min thenPd₂(dba)₃ (366 mg, 0.4 mmol) was added and the mixture was heated atreflux for 3 d. The reaction mixture was diluted with H₂O (100 mL). Theaqueous layer was separated, and washed with CH₂Cl₂ (3×40 mL). Theaqueous layer was adjusted the pH to 5.8 by using 1N HCl. Someprecipitate appeared. The mixture was stored in a freezer overnight. Theprecipitate was collected and dried to obtain 114 (450 mg, 41%): mp246-249° C. (dec.); ¹H NMR (500 MHz, CD₃OD+NaOD) δ 7.84 (s, 2H), 7.64(s, 1H), 7.54-7.63 (m, 4H), 7.39 (s, 2H), 6.08 (bs, 1H), 4.85 (bs, 2H),4.73 (s, 1H), 3.76 (m, 1H), 2.74 (m, 1H), 1.99 (s, 2H), 1.88 (s, 2H),1.63 (d, 6H), 1.21-1.36 (m, 4H); CI MS m/z=500 [C₂₈H₃₃N₇O₂+H]⁺.

Example 98 Preparation of Compound 115

[1470] To a cooled MeOH (20 mL) solution was slowly added TMSCl (253 μL,2.0 mmol). The solution was stirred 20 min, followed by the addition of114 (100 mg, 0.2 mmol). The reaction mixture was stirred at roomtemperature for 24 h. The reaction mixture was cooled with an ice-waterbath then Et₃N (557 mL) was added. The mixture was concentrated invacuo, to provide the crude product, which was washed with water (2×20mL). The residue was purified by chromatography on a silica gel. Afterremoval of the solvent and drying in vacuo, the residue was dissolved inMeOH (5 mL), followed by the addition of ether (10 mL). The precipitatewas collected and dried to provide 115 (75 mg, 73%): mp 194-197° C.; ¹HNMR (500 MHz, CD₃OD) δ 8.07 (d, 2H), 7.80 (s, 1H), 7.72 (d, 2H), 7.63(d, 2H), 7.46 (d, 2H), 4.63-4.79 (m, 1H), 3.91 (s, 3H), 3.65-3.77 (m,1H), 3.07 (bs, 1H), 2.12 (d, 2H), 2.01 (d, 2H), 1.55 (d, 6H), 1.29-1.49(m, 4H); API MS m/z=514 [C₂₉H₃₅N₇O₂+H]⁺.

Example 99 Preparation of Compound 117

[1471] To a suspension of compound 114 (250 mg, 0.50 mmol), pyridine (60μL, 0.75 mmol), and DMAP (6.1 mg, 0.05 mmol) in H₂O-dioxane (2:1, 40 mL)was added Ac₂O (57 μL, 0.60 mmol). After stirring 4 h at roomtemperature, K₂CO₃ (100 mg) was added followed by additional Ac₂O (100μL). The reaction mixture was stirred 2 h at room temperature. Water (50mL) was added and the pH was adjusted to 5. The precipitate wascollected, washed with water and ether, and dried in vacuo. Theprecipitate (200 mg) was added to a solution of TMSCl (500 μL, 3.94mmol) in MeOH (25 mL). The reaction mixture was stirred 24 h at roomtemperature. The mixture was concentrated in vacuo. The product waspurified by silical gel chromatography to provide 117 (145 mg, 52%): mp247-250° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.09 (d, 2H), 7.64 (d, 2H), 7.58(d, 2H), 7.49 (s, 1H), 7.45 (d, 2H), 5.91 (bs, 1H), 5.18 (d, 1H), 4.83(bs, 2H), 4.61-4.68 (m, 2H), 3.93 (s, 3H), 3.67-3.78 (m, 2H), 3.07 (bs,1H), 2.16 (d, 2H), 2.02 (d, 2H), 1.95 (s, 3H), 1.54 (d, 6H), 1.23-1.32(m, 4H); API MS m/z=556 [C₃₁H₃₇N₇O₃+H]⁺.

Example 100 Preparation of Compound 116

[1472] To a solution of compound 117 (90 mg, 0.16 mmol) in MeOH—H₂O(6:1, 23 mL) was added KOH (11 mg, 0.19 mmol) in 5 mL MeOH. The reactionmixture was refluxed for 24 h. After removal of the solvent the residuewas dissolved in 15 mL of water and washed with CH₂Cl₂. The aqueouslayer was separated and adjusted pH to 4.5 by using 1N HCl. Theprecipitate was collected and dried to obtain 116 (60 mg, 68%): mp344-347° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.21 (bs, 1H), 8.14 (d, 2H),7.64-7.88 (m, 6H), 7.47 (d, 2H), 6.06 (bs, 1H), 5.18 (d, 1H), 4.85 (bs,2H), 4.51-4.66 (m, 1H), 3.62 (bs, 1H), 3.46 (bs, 1H), 1.89 (bs, 2H),1.77 (bs, 5H), 1.95 (s, 3H), 1.47 (d, 6H), 1.23-1.36 (m, 4H); API MSm/z=542 [C₃₀H₃₅N₇O₃+H]⁺.

Example 101 Preparation of Compound 118

[1473] Compound 61 (1.0 g, 2.18 mmol), 3-carboxyphenylboronic acid (1.0g, 6.03 mmol), 2N Na₂CO₃ (5 mL), and DME/EtOH (50 mL) were mixedtogether and degassed with N₂ for 1 h. Pd₂(dba)₃ (366.0 mg, 0.4 mmol)and PPh₃ (330.0 mg, 1.26 mmol) were added and the reaction mixture washeated to reflux for 48 h. The reaction mixture was cooled to roomtemperature, diluted with CH₂Cl₂ (50 mL), and extracted with aqueous 5%Na₂CO₃ (3×30 mL). The combined washes were extracted with CH₂Cl₂ (3×30mL) and ether (40 mL). The aqueous phase was neutralized to a pH of 5.8using 1N HCl and kept in a freezer for 1 h. The precipitate wascollected, suspended in MeOH (30 mL) and the insolubles were removed byfiltration. To the MeOH solution was added ether (20 mL) to precipitatethe product. The white solid was collected and dried in vacuo to offer118 (65 mg, 6%): mp 205-208° C.; ¹H NMR (500 MHz, CD₃OD+NaOD) δ 8.17 (s,1H), 7.88 (d, 1H), 7.80 (s, 1H), 7.56-7.63 (m, 3H), 7.35-7.41 (m, 3H),6.08 (bs, 1H), 4.80 (bs, 2H), 4.59-4.75 (m, 1H), 3.72-3.82 (m, 1H),2.89-3.01 (m, 1H), 1.90-1.99 (m, 4H), 1.51 (d, 6H), 1.29-1.40 (m, 2H),1.12-1.23 (m, 2H); API MS m/z=500 [C₂₈H₃₃N₇O₂+H]⁺.

Example 102 Preparation of Compound 119

[1474] 3-Thiopheneboronic acid (4.5 g, 35.2 mmol) and6-chloronicotinamide (5.0 g, 32.0 mmol) were dissolved in DMA (150 mL),followed by the addition of 2N Na₂CO₃ (23 mL). N₂ gas was passed throughthe mixture for 1 h. Pd(PPh₃)₄ (0.74 g, 0.64 mmol) was added and thereaction mixture was heated to reflux for 24 h. The reaction mixture wascooled to room temperature and poured into an ice-water (1 L) andstirred for 10 min. The precipitate was collected and washed withacetone. The collected solid was suspended in EtOAc (150 mL) and heatedto reflux for 5 min. The solid was filtered and collected. After dryingin vacuo, 119 (4.5 g, 69%) was obtained: ¹H NMR (500 MHz, DMSO-d₆) δ9.08 (s, 1H), 8.34 (s, 1H), 8.28 (d, 1H), 8.20 (bs, 1H), 7.99 (d, 1H),7.81 (d, 1H), 7.71 (d, 1H), 7.60 (bs, 1H).

Example 103 Preparation of Compound 120

[1475] To compound 119 (4.08 g, 20.0 mmol) suspended in THF (50 mL), wasadded 1M BH₃-THF (164 mL). The mixture was heated to reflux for 9 h. Themixture was cooled with an ice-water bath and adjusted to a pH of 1-2,and stirred for 1 h at room temperature. The pH was adjusted to 9-10 (2NNaOH) and extracted with EtOAc (3×50 mL). The combined organic phaseswere washed with H₂O (50 mL), brine (50 mL), and dried over Na₂SO₄.After filtration and removal of the solvent, the residue was dissolvedin EtOH (50 mL), followed by the addition of 1M HCl/ether (20 mL). Themixture was concentrated to dryness to provide 120 (2.03 g, 45%): ¹H NMR(500 MHz, CD₃OD) δ 8.93 (s, 1H), 8.61 (d, 1H), 8.51 (s, 1H), 8.43 (d,1H), 7.81 (d, 1H), 7.70 (d, 1H), 3.30 (t, 2H).

Example 104 Preparation of Compound 121

[1476] Compound 120 (2 g, 8.82 mmol), 2,6-dichloropurine (1.5 g, 8.01mmol), EtOH (50 mL), and (i-Pr)₂NEt (3.8 mL, 22 mmol) were heated atreflux for 16 h. The reaction mixture was then cooled with an ice-waterbath. The precipitate was collected and washed with EtOH, H₂O, andether. The precipitate was dried in vacuo to obtain 121 (0.84 g, 31%):¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (bs, 1H), 8.76 (bs, 1H), 8.63 (s, 1H),8.07 (bs, 2H), 7.79 (bs, 2H), 7.71 (d, 1H), 7.64 (d, 1H), 4.68 (bs, 2H).

Example 105 Preparation of Compound 122

[1477] Compound 121 (950 mg, 2.77 mmol) was dissolved in DMSO (50 mL),and then K₂CO₃ (2.07 g, 15.0 mmol) was added, followed by the additionof 2-iodopropane (830 L, 8.31 mmol). The reaction mixture then wasstirred at room temperature overnight. The reaction mixture was pouredinto an ice-water bath (400 mL), stirred for 10 min, and extracted withEtOAc (4×50 mL). The combined organic phases were washed with H₂O (40mL), brine (40 mL), and dried over MgSO₄. After filtration and removalof the solvent, the residue was dissolved in hot EtOAc (40 mL), followedby the addition of hexanes (80 mL). The precipitate was collected anddried in vacuo to obtain 122 (798 mg, 90%): ¹H NMR (500 MHz, CDCl₃) δ8.64 (s, 1H), 7.83 (s, 1H), 7.70-7.79 (m, 2H), 7.60 (d, 1H), 7.55 (d,1H), 7.36 (d, 1H), 6.11 (bs, 1H), 4.77-4.96 (m, 3H), 1.53 (d, 6H).

Example 106 Preparation of Compound 123

[1478] Compound 122 (780.0 mg, 2.03 mmol), trans-1,4-diaminocyclohexane(2.3 g, 20.3 mmol), and EtOH (4 mL) were heated in a sealed tube to 150°C. for 20 h. The reaction mixture was poured into ice-water (150 mL) andstirred for 10 min. The resulting precipitate was washed with H₂O (2×20mL) and dried. The solid was chromatographed on a silica gel column.After removal of the solvent and drying in vacuo, 123 (765 mg) wasobtained: mp 78-81° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.63 (s, 1H), 7.87 (s,1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.55 (d, 1H), 7.04-7.09 (m, 1H), 6.92(s, 1H), 5.95 (bs, 1H), 4.64 (bs, 2H), 4.33-4.45 (m, 2H), 3.74-3.77 (m,1H), 2.67-2.76 (m, 1H), 2.13 (d, 2H), 1.90 (d, 2H), 1.63 (bs, 2H), 1.54(d, 6H), 1.19-1.30 (m, 4H); ¹³C NMR (CDCl₃) δ 159.1, 155.0, 152.7,151.3, 149.3, 143.3, 142.3, 136.2, 134.8, 133.4, 126.4, 126.4, 123.5,120.2, 114.8, 50.4, 50.3, 46.5, 42.0, 35.7, 32.3, 22.8; API MS m/z=463[C₂₄H₃₀N₈S+H]⁺.

Example 107 Preparation of Compound 124

[1479] To an ice-cold solution of compound 123 (420 mg, 0.91 mmol) inCH₂Cl₂ (20 mL) was added pyridine (110 1L, 1.4 mmol), DMAP (11.0 mg,0.09 mmol) and Ac₂O (94.2 μL, 1 mmol). The reaction mixture was stirredfor 30 min at 0° C., followed by 2 h at room temperature. After removalof the solvent, the residue was chromatographed on a silica gel column.The resulting solid was recrystallized with EtOAc/MeOH and dried invacuo to give 124 (350 mg, 79%): mp 249-252° C.;

[1480]¹H NMR (500 MHz, CDCl₃) δ 8.61 (s, 1H), 7.85 (s, 1H), 7.70 (d,1H), 7.62 (d, 1H), 7.53 (d, 1H), 7.48 (s, 1H), 7.38 (d, 1H), 6.00 (bs,1H), 5.25 (d, 1H), 4.77 (bs, 2H), 4.53-4.72 (m, 2H), 3.68-3.77 (m, 2H),2.10 (d, 2H), 2.00 (d, 2H), 1.94 (s, 3H), 1.52 (d, 6H), 1.17-1.28 (m,4H); ¹³C NMR (CDCl₃) δ 169.4, 159.0, 155.0, 152.8, 149.2, 142.8, 142.3,136.1, 134.9, 133.4, 126.5, 126.4, 123.5, 120.2, 114.9, 50.1, 48.3,46.5, 42.2, 32.2, 32.1, 22.8; API MS m/z=505 [C₂₆H₃₂N₈OS+H]⁺.

Example 108 Alternative Preparation of Compound 71

[1481] To a solution of 4-phenylbenzoic acid (5.46 g, 27.6 mmol) inmethylene chloride (66 mL) was added 2 drops of DMF and oxalyl chloride(2.80 mL, 30.3 mmol). The reaction mixture was stirred overnight andadded to a stirred solution of ice and ammonium hydroxide. The resultingprecipitate was filtered, washed with methylene chloride, and trituratedwith water. The product was collected by filtration and dried in vacuoto yield 4-phenylbenzamide (3.88 g, 71%).

[1482] Under a nitrogen atmosphere, 4-phenylbenzamide (2.01 g, 10.2mmol) was dissolved in THF (50 mL) and heated to reflux. To the mixturewas added dropwise 1 M borane in THF (80.0 mL, 80.0 mmol). Afterrefluxing for 18 h, the reaction mixture was cooled to room temperatureand treated with 1 N HCl (40 mL). The solution was made basic viaaddition of 3 N NaOH (60 mL) and extracted with ethyl acetate (3×370mL). The extract was washed with brine and dried over sodium sulfate.Concentration yielded 4-phenylbenzyl amine as a white solid (1.73 g,93%).

[1483] 4-Phenylbenzyl amine (1.73 g, 10.1 mmol) and 2,6-dichloropurine(1.94 g, 10.1 mmol) was dissolved in water (110 mL). To the solution wasadded N,N-diisopropylethylamine (3.54 mL, 20.2 mmol). The reactionmixture was heated to reflux for 5 h and cooled to room temperature. Aprecipitate was collected by filtration. The solid was washed with waterand ethanol and dried to yield 71 (2.35 g, 69%): ¹H NMR (300 MHz,(CD₃)₂SO) δ 8.69 (brs, 1H), 8.15 (s, 1H), 7.57-7.68 (m, 4H), 7.30-7.50(m, 5H), 4.71 (d, 2H).

Example 109 Preparation of Compound 126

[1484] To a stirred solution of 3-iodobenzylamine (5.00 g, 21.4 mmol) in10 water (100 mL) was added 2,6-dichloropurine (4.04 g, 21.4 mmol) andN,N-diisopropylethylamine (7.47 mL, 42.5 mmol). The mixture was refluxedfor 5 h and stored at room temperature overnight. The resultingsuspension was filtered. The filter cake was triturated with water (3×25mL) and ethanol (2×15 mL) and dried under high vacuum to yield 126 (7.49g, 91%): ¹H NMR (300 MHz, (CD₃)₂SO) δ 8.50-8.80 (brs, 1H), 8.17 (s, 1H),7.75 (s, 1H), 7.61 (d, 1H), 7.37 (d, 1H), 7.14 (t, 1H), 5.14 (brs, 1H),4.61 (d, 2H).

Example 110 Preparation of Compound 127

[1485] The purine derivative 126 (7.00 g, 18.2 mmol) was dissolved indimethylsulfoxide (120 mL). To this stirred solution was added potassiumcarbonate (20.0 g, 145 mmol) and 2-iodopropane (7.28 mL, 72.8 mmol). Thereaction mixture was stirred under a nitrogen atmosphere for 20 h beforebeing poured into stirred water (600 mL). After 10 min, the resultingmixture was extracted with ethyl acetate (4×95 mL). The combined organiclayers were washed with water (25 mL) and brine (3×25 mL), dried oversodium sulfate, and concentrated in vacuo. The resulting material waspurified by recrystallization from ethyl acetate in hexanes to yield 127(7.51 g, 97%): mp 147-152° C.; ¹H NMR (300 MHz, (CD₃)₂SO) δ 8.84 (m,1H), 8.31 (s, 1H), 7.74 (s, 1H), 7.60 (d, 1H), 7.36 (d, 1H), 7.13 (t,1H), 4.51-4.75 (m, 3H), 1.50 (d, 6H); API MS m/z=429 [C₁₅H₁₅ClN₅+H]⁺.

Example 111 Preparation of Compound 128

[1486] In a sealed tube, 127 (2.57 g, 6.00 mmol),trans-1,4-diaminocyclohexane (6.85 g, 60.0 mmol), and ethanol (10 mL)were combined. The reaction mixture was heated to 160° C. for 24 h.After cooling to room temperature, the mixture was filtered. Thefiltrate was concentrated and diluted with ethyl acetate (250 mL). Theorganic solution was washed with water (250 mL) and saturated sodiumbicarbonate solution (2×250 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated. A portion of the resulting crudeproduct was purified via silica gel chromatography to yield 128 (181mg): ¹H NMR (300 MHz, (CD₃)₂SO) δ 7.87 (brs, 1H), 7.78 (s, 1H), 7.70 (s,1H), 7.55 (d, 1H), 7.35 (d, 1H), 7.09 (t, 1H), 6.06 (d, 1H), 4.43-4.70(m, 3H), 3.58 (brs, 1H), 1.66-1.94 (m, 4H), 1.46 (d, 6H), 1.00-1.30 (m,4H); ESI MS m/z=506 [C₂₁H₂₈N₇+H]⁺.

Example 112 Preparation of Compound 129

[1487] The amine 127 (6.06 g, 6.00 mmol) was dissolved in a mixture oftetrahydofuran (45 mL) and water (15 mL). To this stirred mixture wereadded sodium bicarbonate (2.02 g, 24.0 mmol) anddi-tert-butyldicarbonate (2.90 g, 13.3 mmol). After 3.5 h, the solutionwas extracted with methylene chloride (3×75 mL). The organic extractswere combined, washed with brine (225 mL), and dried over sodiumsulfate. The organic liquid was concentrated and the resulting materialwas purified via silica gel chromatography (33:67 to 50:50 to 60:40ethyl acetate/hexanes) to yield 129 (4.94 g, 68%): ¹H NMR (300 MHz,CDCl₃) δ 7.72 (s, 1H), 7.58 (d, 1 H), 7.46 (s, 1H), 7.30 (d, 1H), 7.02(t, 1H), 4.50-4.76 (m, 4H), 4.40 (m, 1H), 3.70 (brs, 1H), 3.43 (brs,1H), 1.90-2.20 (m, 4H), 1.51 (d, 6H), 1.45 (s, 9H), 1.13-1.35 (m, 4H);API MS m/z=607 [C₂₆H₃₆N₇O₂+H]⁺.

Example 113 Preparation of Compound 130

[1488] To a stirred solution of 129 (1.00 g, 1.65 mmol) in ethyleneglycol dimethyl ether (40 mL) was added 3-thiopheneboronic acid,triphenylphosphine (250 mg, 0.950 mmol), and 2 M sodium carbonatesolution (3.8 mL). The mixture was purged with nitrogen for 10 min andtris(dibenzylideneacetone)dipalladium(0) (64.0 mg, 0.060 mmol) wasadded. After refluxing overnight under nitrogen, the reaction mixturewas cooled to room temperature and diluted with water (100 mL). Theresulting solution was extracted with methylene chloride (3×50 mL). Theorganic extracts were combined, washed with brine (30 mL), and driedover sodium sulfate. The organic liquid was filtered and concentrated invacuo. Purification via silica gel chromatography (50:50 ethylacetate/hexanes) yielded 130 (0.87 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ7.23-7.30 (m, 8H), 6.02 (brs, 1H), 4.78 (d, 2H), 4.53-4.68 (m, 1H), 4.32(m, 1H), 3.70 (m, 1H), 3.28-3.55 (m, 1H), 1.80-2.19 (m, 4H), 1.53 (d,6H), 1.45 (s, 9H), 1.05-1.32 (m, 4H); ESI MS m/z=562 [C₃₀H₃₉N₇O₂S+H]⁺.

Example 114 Preparation of Compound 131

[1489] To a solution of 130 in EtOAc was added 1 N HCl. Afterconcentration of the solution, isolate 131 (658 mg, 91%): mp 211-216°C.; ¹H NMR (300 MHz, CD₃OD) δ 8.40 (brs, 1H), 7.25-7.85 (m, 7H),4.60-5.10 (m, 5H), 3.91 (m, 1H), 3.16 (m, 1H), 1.94-2.33 (m, 4H),1.32-1.79 (m, 10H); ESI MS m/z=462 [C₂₅H₃₁N₇S+H]⁺.

Example 115 Preparation of Compound 132

[1490] Following procedures outlined above for acetylation, prepared 132from 131 (352 mg, 80%): mp 209-211° C.; ¹H NMR (300 MHz, CDCl₃) δ7.27-7.67 (m, 8H), 6.25 (brs, 1H), 5.19 (d, 1H), 4.79 (d, 2H), 4.52-4.67(m, 2H), 3.69 (m, 2H), 2.09 (m, 2H), 1.88-1.98 (m, 5H), 1.50 (d, 6H),1.06-1.33 (m, 4H); ESI MS m/z=504 [C₂₇H₃₃N₇OS+H]⁺.

Example 116 Preparation of Compound 133

[1491] Following general procedures outilined above for Suzuki Couplingreaction, prepared 133 from 129 (0.61 g, 67%): ¹H NMR (300 MHz, CDCl₃) δ7.30-7.62 (m, 10H) 6.00 (brs, 1H), 4.83 (d, 2H), 4.54-4.70 (m, 2H), 4.37(m, 1H), 3.71 (m, 1H), 3.39 (m, 1H), 2.12 (m, 2H), 2.47 (m, 2H), 1.53(d, 6H), 1.45 (s, 9H), 1.19 (m, 4H); ESI MS m/z=556 [C₃₂H₄₁N₇O₂+H]⁺.

Example 117 Preparation of Compound 134

[1492] To a stirred solution of 133 (530 mg, 0.950 mmol) in methanol (3mL) was added 1 N HCl in diethyl ether (9.50 mL, 9.50 mmol). Afterstirring for 3.5 h, hydrogen chloride gas was gently bubbled through thesolution. After 20 min, the solution was concentrated in vacuo. Theresulting material was recrystallized from methanol in ether to afford134 in quantitative yield: ¹H NMR (300 MHz, CD₃OD) δ 8.33 (brs, 1H),7.67 (s, 1H), 7.52-7.64 (m, 3H), 7.29-7.50 (m, 5H), 4.80-5.00 (m, 4H),4.72 (m, 1H), 3.87 (m, 1H), 3.14 (m, 1H), 2.02-2.25 (m, 4H), 1.59 (d,6H), 1.47 (m, 4H); ESI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 118 Preparation of Compound 135

[1493] Following procedures outlined above for acetylation, prepared 135from 134 (195 mg, 82%): mp 183-185° C.; ¹H NMR (300 MHz, CDCl₃) δ7.30-7.64 (m, 10H), 6.19 (brs, 1H), 5.12 (d, 1H), 4.81 (d, 2H), 4.60 (m,2H), 3.68 (m, 2H), 2.09 (m, 2H), 1.86-1.99 (m, 5H), 1.51 (d, 5H),1.04-1.32 (m, 4H); ESI MS m/z 498 [C₂₉H₃₅N₇O+H]⁺.

Example 119 Preparation of Compound 136

[1494] To a mixture of 71 (2.00 g, 5.96 mmol) in dimethylsulfoxide (44mL) was added potassium carbonate (6.56 g, 47.7 mmol) and iodoethane(2.00 mL, 24.4 mmol). After stirring overnight, the reaction mixture waspoured into a stirred solution of water (300 mL). After 2 d, it wasfiltered. The filtrate was extracted with ethyl acetate (2×180 mL). Theorganic extracts were combined and washed with brine (150 mL). Theorganic layer was dried over magnesium sulfate. Concentration afforded136 (1.90 g, 88%).

Example 120 Preparation of Compound 137

[1495] In a sealed tube, 136 (0.60 g, 1.66 mmol),trans-1,4-diaminocyclohexane (1.93 g, 16.8 mmol), and potassium iodide(10 mg), were dissolved in ethanol (18 mL). The mixture was heated to160° C. After 4 d, the mixture was cooled to room temperature andfiltered. The filtrate was dissolved in ethyl acetate and washed withwater (2×100 mL) and brine (100 mL). The organic layer was dried overmagnesium sulfate, filtered, and concentrated. The material was purifiedby silica gel chromatography and recrystallization from ethanol inhexanes (1:10) to yield 137 (886 mg, 41%): mp 175-182° C.; ¹H NMR (500MHz, CD₃OD) δ 7.30-7.75 (m, 10H), 4.55-4.95 (m, 4H), 4.10 (q, 2H), 3.78(m, 1H), 2.99 (m, 1H), 2.11 (d, 2H), 1.99(d, 2H), 1.44(m, 3H), 1.31 (m4H); ESI MS m/z=442 [C₂₆H₃₁N₇+H]⁺.

Example 121 Preparation of Compound 138

[1496] Compound 71 (2.02 g, 6.02 mmol), iodomethane (1.50 mL, 24.4mmol), and potassium carbonate were dissolved in dimethylsulfoxide (44mL) and stirred overnight. The reaction mixture was poured into 150 mLof stirring water. The organic and aqueous layers were separated. Theorganic layer was washed with brine (3×100 mL) and dried over magnesiumsulfate. The solids were removed by filtration and the solution wasconcentrated in vacuo to afford 138 (1.93 g, 93%).

Example 122 Preparation of Compound 139

[1497] In a sealed tube, 138 (1.80 g, 5.15 mmol) andtrans-1,4-diaminocyclohexane (5.90 g, 51.7 mmol) were dissolved inethanol (85 mL). The mixture was heated to 140° C. After heatingovernight, the reaction mixture was cooled to room temperature andconcentrated. The resulting solid was dissolved in ethyl acetate (160mL) and washed with water (160 mL) and brine (2×100 mL). The organiclayer was dried over magnesium sulfate and filtered. Concentrationafforded a solid, which was purified by silica gel chromatography andrecrystallization from ethanol in hexanes (1:20) and ethyl acetate inhexanes to yield 139 (850 mg, 38%): mp 182-184° C.; ¹H NMR (500 MHz,CD₃OD) δ 7.25-7.70 (m, 10H), 4.64-4.90 (m, 4H), 3.75 (m, 1H), 3.65 (s,3H), 2.68 (m, 1H), 2.05 (m, 2H), 1.88 (m, 2H), 1.25 (m, 4H); ESI MSm/z=428 [C₂₅H₂₉N₇+H]⁺.

Example 123 Preparation of Compound 140

[1498] The HCl salt of 139 (86.7 mg, 0.162 mmol) was suspended inmethylene chloride (20 mL). The suspension was immersed in an ice bathwhile triethylamine (0.16 mL, 1.12 mmol) and a catalytic amount of DMAPwere added. Acetyl chloride (0.04 mL, 0.560 mmol) was added to themixture. The reaction was quenched by the addition of 5% aqueous NaHCO₃solution (50 mL). The aqueous layer was extracted with methylenechloride (2×50 mL). The extracts were washed with brine (100 mL), driedover magnesium sulfate, filtered, and concentrated. The resulting solidmaterial was dried in vacuo. Purification by silica gel chromatographyand recrystallization from ethyl acetate in hexanes (5:60) afforded 140(6.4 mg, 8%):

[1499]¹H NMR (300 MHz, CD₃OD) δ 7.50-7.68 (m, 5H), 7.25-7.47 (m, 5H),5.22 (m, 3H), 4.20-5.05 (m, 2H), 3.75 (m, 1H), 3.65 (s, 3H), 3.35-3.47(m, 1H), 2.78 (m, 1H), 1.95-2.16 (m, 2H), 1.80-1.95 (m, 2H), 1.17-1.40(m, 4H).

Example 124 Preparation of Compound 144

[1500] Compound 71 (2.03 g, 5.96 mmol), 1-iodopropane (2.25 mL, 24.4mmol), and potassium carbonate (6.61 g, 47.7 mmol) were dissolved indimethylsulfoxide (44 mL) and allowed to stir overnight. The reactionmixture was added to 300 mL of stirring water and stirred for 2 d. Theresulting precipitate was collected by filtration and dried in vacuo toafford 141 (2.07 g, 92%).

Example 125 Preparation of Compound 142

[1501] In a sealed tube, 141 (1.82 g, 4.81 mmol) andtrans-1,4-diaminocyclohexane (5.67 g, 49.7 mmol) were dissolved inethanol (53 mL). The mixture was heated to 140° C. for 3 d. Aftercooling to room temperature, the reaction mixture was concentrated anddissolved in ethyl acetate (100 mL). This solution was washed with water(100 mL) and brine (2×100 mL). The organic layer was dried overmagnesium sulfate, filtered, and concentrated. The product was purifiedby silica gel chromatography and recrystallizations from ethanol inhexanes (1:20) to yield 142 (523 mg, 24%): mp 133-138° C.; ¹H NMR (500MHz, CD₃OD) δ 7.25-7.70 (m, 10H), 4.65-4.85 (m, 4H), 4.02 (t, 2H), 3.76(m, 1H), 2.85 (m, 1H), 2.08 (d, 2H), 1.94 (d, 2H), 1.86 (q, 2H),1.20-1.42 (m, 4H), 0.93 (t, 3H); ESI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 126 Preparation of Compound 143

[1502] Compound 71 (2.01 g, 5.98 mmol), iodocyclopentane (2.80 mL, 24.2mmol), and potassium carbonate (6.75 g, 48.9 mmol) were dissolved indimethylsulfoxide (44 mL) and allowed to stir under nitrogen overnight.The reaction mixture was added to 150 mL of stirring water and dilutedwith 150 mL ethyl acetate. The organic and aqueous phases wereseparated. The organic phase was washed with brine (3×100 mL) and driedover magnesium sulfate. After filtering, the organic liquid wasconcentrated and the resulting solid was dried in vacuo to afford 143(1.29 g, 55%).

Example 127 Preparation of Compound 144

[1503] In a sealed tube, 143 (304 mg, 0.749 mmol) andtrans-1,4-diaminocyclohexane (891 mg, 7.80 mmol) were dissolved inethanol (10 mL). The mixture was heated to 140° C. for 4 d. Aftercooling to room temperature, the reaction mixture was diluted with ethylacetate (160 mL). This solution was washed with water (160 mL) and brine(2×100 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated. The material was purified by silica gelchromatography and recrystallizations from ethanol in hexanes (1:20) toyield 144 (299 mg, 19%): mp 144-146° C.; ¹H NMR (500 MHz, CD₃OD) δ7.28-7.75 (m, 10H), 4.68-4.85 (m, 4H), 3.75 (m, 1H), 2.82 (m, 1H),1.70-2.25 (m, 13H), 1.20-1.43 (m, 4H); ESI MS m/z=482 [C₂₉H₃₅N₇+H]⁺.

Example 128 Preparation of Compound 145

[1504] Compound 71 (2.01 g, 5.98 mmol), allylbromide (2.10 mL, 24.4mmol), and potassium carbonate (6.61 g, 47.8 mmol) were dissolved indimethylsulfoxide (44 mL) and stirred overnight. The reaction mixturewas added to 150 mL of stirring water and diluted with 150 mL ethylacetate. The organic and aqueous phases were separated. The organicphase was washed with brine (3×100 mL), dried over magnesium sulfate,filtered, and concentrated. The resulting solid was dried in vacuo toafford 145 (1.98 g, 88%).

Example 129 Preparation of Compound 146

[1505] In a sealed tube, 145 (1.99 mg, 5.29 mmol),trans-1,4-diaminocyclohexane (6.21 g, 54.3 mmol), and2,6-di-tert-butylphenol (1.13 g, 5.48 mmol) were dissolved in ethanol(60 mL). The mixture was heated to 140° C. for 4 d. After cooling toroom temperature, the reaction was concentrated and diluted with ethylacetate (175 mL). This organic solution was washed with water (175 mL)and brine (2×100 mL) and concentrated. The product was purified bysilica gel chromatography and recrystallizations from ethanol in hexanes(1:20) to yield 146 (432 mg, 18%): mp 111-114° C.; ¹H NMR (300 MHz,CD₃OD) δ 7.25-7.72 (m, 10H), 5.95-6.10 (m, 1H), 5.21 (d, 1H), 5.10 (d,1H), 4.82 (m, 2H), 4.77 (s, 2H), 4.67 (d, 2H), 3.75 (m, 1H), 2.87 (m,1H), 2.07 (d, 2H), 1.92 (d, 2H), 1.15-1.47 (m, 4H); ESI MS m/z=454[C₂₇H₃₁N₇+H]⁺.

Example 130 Preparation of Compound 147

[1506] Compound 71 (2.07 g, 6.17 mmol), 2-iodobutane (3.10 mL, 26.9mmol), and potassium carbonate (6.78 g, 49.1 mmol) were dissolved indimethylsulfoxide (44 mL) and allowed to stir under nitrogen overnight.The reaction mixture was diluted with ethyl acetate (300 mL). Theorganic material was washed with water (200 mL) and brine (300 mL) anddried over magnesium sulfate. After filtration, the material wasconcentrated and the resulting solid was dried in vacuo to afford 147(1.29 g, 55%).

Example 131 Preparation of Compound 148

[1507] In a sealed tube, 147 (1.29 g, 3.30 mmol) andtrans-1,4-diaminocyclohexane (3.80 g, 33.2 mmol) were dissolved inethanol (70 mL). The mixture was heated to 140° C. After 4 d, thereaction was cooled to room temperature, concentrated, and dissolved inethyl acetate (160 mL). This solution was washed with water (160 mL) andbrine (2×100 mL) and dried over magnesium sulfate. The organic liquidwas filtered and concentrated. The resulting solid was dried in vacuoand purified by silica gel chromatography and recrystallizations fromethanol in hexanes (1:40) to yield 148 (229 mg, 15%): mp 146-150° C.; ¹HNMR (500 MHz, CD₃OD) δ 7.70 (s, 1H), 7.25-7.60 (m, 9H), 4.65-4.90 (m,4H), 4.37 (m, 1H), 3.74 (m, 1H), 2.86 (m, 1H), 1.82-2.15 (m, 6H), 1.50(d, 3H), 1.20-1.43 (m, 4H), 0.87 (t, 3H).

Example 132 Preparation of Compound 149

[1508] To a solution of 61 (0.90 g, 1.96 mmol) in ethylene glycoldimethyl ether (54 mL), were added 3,5-dimethylphenylboronic acid (0.59g, 3.93 mmol), triphenylphosphine (0.26 g, 0.99 mmol), and 2 M sodiumcarbonate solution (10 mL). The solution was refluxed for 20 min andcooled to room temperature. Tris(dibenzylideneacetone)dipalladium(0)(0.66 g, 0.072 mmol) was added and the reaction returned to reflux.After refluxing overnight, the reaction mixture was cooled to roomtemperature and another 100 mg 3,5-dimethylphenylboronic acid wereadded. After refluxing for another 5 h, the reaction was quenched with50 mL water. The aqueous solution was extracted with methylene chloride(3×50 mL). The extracts were combined and washed with water (50 mL) andbrine (50 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated. The product was purified by silica gelchromatography to yield 149: mp 86-90° C.; ¹H NMR (300 MHz, CDCl₃) δ7.34-7.58 (m, 5H), 7.20 (s, 2H), 6.97 (s, 1H), 5.93 (brs, 1H), 4.54-4.90(m, 4H), 3.66-3.85 (m, 1H), 2.70 (m, 1H), 2.37 (s, 6H), 2.05-2.20 (m,4H), 1.80-1.95 (m, 2H), 1.54 (d, 6H), 1.10-1.35 (m, 4H); API MS m/z=484[C₂₉H₃₇N₇+H]⁺.

Example 133 Preparation of Compound 150

[1509] To a stirred, 0° C. solution of 149 (500 mg, 0.97 mmol) inmethylene chloride (20 mL), were added pyridine (120 μL), DMAP (11.8 mg,0.097 mmol), and acetic anhydride (91 μL, 0.097 mmol). After 40 min, thereaction mixture was warmed to room temperature and stirred for 3 h.Another 100 μL acetic anhydride was added. After 1 h, the solution wasconcentrated and dried in vacuo. The resulting material was purified bysilica gel chromatography (95:5:1 CH₂Cl₂/methanol/NH₄OH) to yield 150(400 mg, 80%): mp 207-210° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.56 (m,3H), 7.36-7.45 (m, 2H), 7.18 (s, 2H), 6.98 (s, 1H), 5.98 (brs, 1H), 5.27(d, 1H), 4.80 (d, 2H), 4.56-4.70 (m, 1H), 3.68-3.84 (m, 1H), 2.37 (s,6H), 1.90-2.23 (m, 7H), 1.54 (d, 6H), 1.15-1.48 (m, 4H); API MS m/z=526[C₃₁H₃₉N₇O+H]⁺.

Example 134 Preparation of Compound 152

[1510] To a solution of 149 (500 mg, 1.03 mmol) in 1,2-dichloroethane (4mL) was added propionaldehyde (90 μL, 1.24 mmol). After stirring for 10min, sodium triacetoxyborohydride (306 mg, 1.44 mmol) was added. Thereaction mixture stirred under nitrogen for 1.5 h before being quenchedwith saturated sodium bicarbonate solution (5 mL). The resultingsolution was extracted with ethyl acetate (3×7 mL). The organic extractswere combined and dried over sodium sulfate. The organic liquid wasfiltered and concentrated. Purification by silica gel chromatography(90:10:1 CH₂Cl₂/methanol/NH₄OH) yielded 152.

Example 135 Preparation of Compound 152 HCl

[1511] To a stirred solution of 152 (120 mg, 0.211 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (127 μL). After 20min, the solution was concentrated and dried in vacuo to yield the HClsalt of 152: ¹H NMR (300 MHz, CD₃OD) δ 8.48 (s, 1H), 7.40-7.68 (m, 4H),7.20 (s, 2H), 6.98 (s, 1H), 4.66-5.07 (m, 3H), 3.80-4.00 (m, 1H),2.90-3.50 (m, 5H), 2.01-2.45 (m 10H), 1.36-1.90 (m, 14H), 1.02 (t, 6H);API MS m/z=568 [C₃₅H₄₉N₇+H]⁺.

Example 136 Preparation of Compound 151

[1512] To a solution of 149 (302 mg, 0.624 mmol) in 1,2-dichloroethane(2.5 mL) was added propionaldehyde (36.0 μL, 0.500 mmol). After stirringfor 15 min under nitrogen, sodium triacetoxyborohydride (93.0 mg, 0.874mmol) was added. After 10 min, another 93.0 mg (0.874 mmol) sodiumtriacetoxyborohydride were added. The reaction mixture stirred undernitrogen for 1.5 h before being quenched with saturated sodiumbicarbonate solution (5 mL). The resulting solution was extracted withethyl acetate (3×7 mL). The organic extracts were combined and driedover sodium sulfate. The organic liquid was filtered and concentrated.Purification by silica gel chromatography (90:10:1CH₂Cl₂/methanol/NH₄OH) yielded 151.

Example 137 Preparation of Compound 151.HCl

[1513] To a stirred solution of 151 (90.0 mg, 0.171 mmol) in ethylacetate (8 mL) was added 2 M HCl in diethyl ether (103 mL). After 20min, the solution was concentrated and dried in vacuo to yield the HClsalt of 151: mp 280-290° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.45 (brs, 1H),7.38-7.67 (m, 4H), 7.29 (s, 2H), 6.97 (s, 1H), 4.63-5.40 (m, 4H),3.78-3.97 (m, 1H), 2.85-3.23 (m, 3H), 2.07-2.44 (m, 8H), 1.32-1.87 (m,14H), 1.02 (t, 3H); API MS m/z=526 [C₃₂H₄₃N₇+H]⁺.

Example 138 Preparation of Compound 153

[1514] To a solution of 61 (2.03 g, 4.44 mmol) in ethylene glycoldimethyl ether (100 mL), was added 2,5-dimethoxyphenylboronic acid (2.42g, 13.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.135 g, 0.148mmol), triphenylphosphine (0.581 g, 2.22 mmol), and 2 M sodium carbonatesolution (10 mL). The dispersion was refluxed overnight under nitrogen.After cooling to room temperature, the reaction mixture was diluted with100 mL water. The aqueous solution was extracted with methylene chloride(3×100 mL). The extracts were combined and washed with water (300 mL)and brine (300 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated. The product was purified by silica gelchromatography (90:10:1 CH₂Cl₂/methanol/NH₄OH) to yield 153 (900 mg,39%).

Example 139 Preparation of 153.HCl

[1515] To a stirred solution of 153 (100 mg, 0.194 mmol) in ethylacetate (10 mL), was added 2 M HCl in diethyl ether (116 μL). After 20min, the solution was concentrated to afford the HCl salt of 153 inquantitative yield: mp 278-288° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.34 (brs,1H), 7.36-7.53 (m, 4H), 6.77-7.01 (m, 3H), 5.30 (brs, 1H), 4.65-5.20 (m,4H), 3.80-3.95 (m, 1H), 3.76 (s, 1H), 3.69 (s, 1H), 3.05-3.22 (m, 1H),2.03-2.30 (m, 4H), 1.35-1.71 (m, 10H); API MS m/z=516 [C₂₉H₃₇N₇O₂+H]⁺.

Example 140 Preparation of Compound 154

[1516] To a 0° C. stirred solution of 153 (300 mg, 0.582 mmol) inmethylene chloride (12 mL) was added pyridine (70 μL), acetic anhydride(54.0 μL, 0.582 mmol), and DMAP (7.10 mg, 0.582 mmol). The solution wasstirred for 40 min before warming to room temperature. After 3 h,another 100 μL acetic anhydride was added. After stirring for 1 h, thereaction mixture was concentrated and dried in vacuo. The material waspurified by silica gel chromatography (90:10:1 CH₂Cl₂/methanol/NH₄OH) toyield 154: mp 185-192° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.78 (s, 1H),7.29-7.45 (m, 4H), 6.87-6.98 (m, 1H), 6.75-6.86 (m, 2H), 4.75 (s, 2H),4.55-4.68 (m, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 1.97-2.13 (m, 2H),1.81-1.96 (m, 5H), 1.53 (d, 6H), 1.21-1.40 (m, 4H); API MS m/z=558[C₃₁H₃₉N₇O₃+H]⁺.

Example 141 Preparation of Compound 155

[1517] To a solution of 153 (242 mg, 0.469 mmol) in 1,2-dichloroethane(1.5 mL) was added propionaldehyde (27.0 μL, 0.375 mmol). After stirringfor 15 min under nitrogen, sodium triacetoxyborohydride (140 mg, 0.657mmol) was added. The reaction mixture was stirred under nitrogenovernight before being concentrated. Purification by silica gelchromatography (90:10:1 CH₂Cl₂/methanol/NH₄OH) yielded 155.

Example 142 Preparation of Compound 155.HCl

[1518] To a stirred solution of 155 (30.0 mg, 0.054 mmol) in ethylacetate (6 mL) was added 2 M HCl in diethyl ether (40.0 μL). After 20min, the solution was concentrated and dried in vacuo to afford the HClsalt of 155 in quantitative yield: mp 264-268° C.; ¹H NMR (300 MHz,CD₃OD) δ 8.41 (brs, 1H), 7.46 (m, 4H), 6.98 (d, 1H), 6.76-6.93 (m, 2H),4.63-5.07 (m, 4H), 3.89 (m, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.13 (m,1H), 2.97 (m, 2H), 2.10-2.35 (m, 4H), 1.35-1.88 (m, 12H), 1.02 (t, 3H);API MS m/z=558 [C₃₂H₄₃N₇O₂+H]⁺.

Example 143 Preparation of Compound 156

[1519] To a solution of 153 (242 mg, 0.469 mmol) in 1,2-dichloroethane(1.5 mL) was added propionaldehyde (27.0 μL, 0.375 mmol). After stirringfor 15 min under nitrogen, sodium triacetoxyborohydride (140 mg, 0.657mmol) was added. The reaction mixture stirred under nitrogen overnightbefore being concentrated. Purification by silica gel chromatography(90:10:1 CHCl₃/methanol/NH₄OH) yielded 156.

Example 144 Preparation of Compound 156.HCl

[1520] To a stirred solution of 156 (160 mg, 0.267 mmol) in ethylacetate (8 mL) was added 2 M HCl in diethyl ether (170 μL). After 20min, the solution was concentrated and dried in vacuo to afford the HClsalt of 156 in quantitative yield: mp 235-243° C.; ¹H NMR (300 MHz,CD₃OD) δ 8.43 (brs, 1H), 7.47 (m, 4H), 6.94-7.04 (d, 1H), 6.80-6.93 (m,2H), 4.67-5.10 (m, 4H), 3.81-3.98 (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H),2.93-3.48 (m, 5H), 2.00-2.35 (m, 4H), 1.36-1.90 (m, 14H), 1.01 (t, 6H);API MS m/z=601 [C₃₅H₄₉N₇O₂+H]⁺.

Example 145 Preparation of Compound 157

[1521] To a solution of 61 (1.50 g, 3.27 mmol) in ethylene glycoldimethyl ether (75 mL), was added 5-methyl-2-thiopheneboronic acid (1.40g, 9.82 mmol), tris(dibenzylideneacetone)dipalladium(0) (100 mg, 0.109mmol), triphenylphosphine (430 mg, 1.64 mmol), and 2 M sodium carbonatesolution (10 mL). The solution was refluxed under nitrogen for 2 d.After cooling to room temperature, the reaction mixture was diluted with100 mL water. The aqueous solution was extracted with methylene chloride(3×100 mL). The extracts were combined and washed with water (300 mL)and brine (300 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated. The product was purified by silica gelchromatography (90:10:1 CHCl₃/methanol/NH₄OH) to yield 157 (1.04 g,67%).

Example 146 Preparation of Compound 157.HCl

[1522] To a stirred solution of 157 (150 mg, 0.269 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (161 μL). After 20min, the solution was concentrated to afford the HCl salt of 157 inquantitative yield: mp 300° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.35 (brs,1H), 7.55 (d, 2H), 7.39 (d 2H), 7.17 (d, 1H), 6.74 (d, 1H), 4.62-5.40(m, 5H), 3.78-3.94 (m, 1H), 3.03-3.20 (m, 1H), 2.47 (s, 3H), 1.98-2.29(m, 4H), 1.44-1.74 (m, 10H); API MS m/z 476 [C₂₆H₃₃N₇S+H]⁺.

Example 147 Preparation of Compound 159

[1523] To a solution of 157 (300 mg, 0.631 mmol) in 1,2-dichloroethane(2.0 mL) was added propionaldehyde (36.0 μL, 0.505 mmol). After stirringfor 30 min under nitrogen, sodium triacetoxyborohydride (190 mg, 0.883mmol) was added. The reaction mixture stirred under nitrogen for 3 hbefore being concentrated. Purification by silica gel chromatography(90:10:1 CHCl₃/methanol/NH₄OH) yielded 159: mp 150-155° C.; ¹H NMR (300MHz, CD₃OD) δ 7.81 (s, 1H), 7.51 (d, 2H), 7.33 (d, 2H), 7.11 (d, 1H),6.73 (d, 1H), 4.80-5.05 (m, 1H), 4.55-4.78 (m, 3H), 3.65-3.80 (m, 1H),3.01 (m, 1H), 2.91 (t, 2H), 2.47 (s, 3H), 2.02-2.19 (m, 4H), 1.60-1.75(m, 8H), 1.54 (d, 6H), 1.19-1.50 (m, 4H), 1.01 (t, 3H); API MS m/z=518[C₂₉H₃₉N₇S+H]⁺.

Example 148 Preparation of Compound 158

[1524] To a 0° C. stirred solution of 157 (300 mg, 0.631 mmol) inmethylene chloride (12 mL) was added pyridine (76 μL), acetic anhydride(58 μL, 0.631 mmol), and DMAP (7.7 mg, 0.063 mmol). After 20 min, thereaction mixture warmed to room temperature. After mixing overnight, thereaction mixture was concentrated and dried in vacuo. The material waspurified by silica gel chromatography (90:10:1 CHCl₃/methanol/NH₄OH) toyield 158: mp 225-230° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.51 (m, 3H),7.32 (d, 2H), 7.07 (d, 1H), 6.71 (m, 1H), 6.14 (brs, 1H), 5.32 (d, 1H),4.53-4.82 (m, 4H), 3.74 (m, 2H), 2.50 (s, 3H), 1.90-2.23 (m, 7H), 1.51(d, 6H), 1.12-1.38 (m, 4H); API MS m/z=518 [C₂₈H₃₅N₇OS+H]⁺.

Example 149 Preparation of Compound 160

[1525] To a suspension of 61 (1.00 g, 2.18 mmol) in ethylene glycoldimethyl ether (50 mL), was added 4-methylthiophene-2-boronic acid (0.93g, 6.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (67.0 mg, 0.073mmol), triphenylphosphine (287 mg, 1.09 mmol), and 2 M sodium carbonatesolution (10 mL). The solution was refluxed under nitrogen for 2 d.After cooling to room temperature, the reaction mixture was diluted with100 mL water. The aqueous solution was extracted with methylene chloride(3×100 mL). The extracts were combined and washed with water (300 mL)and brine (300 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated. The product was purified by silica gelchromatography (90:10:1 CHCl₃/methanol/NH₄OH) to yield 160 (450 mg,44%).

Example 150 Preparation of Compound 160.HCl

[1526] To a stirred solution of 160 (50.0 mg, 0.105 mmol) in ethylacetate (4 mL) was added 2 M HCl in diethyl ether (100 μL). After 20min, the solution was concentrated to afford the HCl salt of 160 inquantitative yield: mp 308-315° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.31 (brs,1H), 7.60 (d, 2H), 7.39 (d, 2H), 7.20 (s, 1H), 6.94 (s, 1H), 4.65-5.10(m, 3H), 3.86 (m, 1H), 3.13 (m, 1H), 2.26 (s, 3H), 2.00-2.12 (m, 4H),1.32-1.72 (m, 10H); API MS m/z=476 [C₂₆H₃₃N₇S+H]⁺.

Example 151 Preparation of Compounds 162 and 163

[1527] To a stirred solution of 160 (300 mg, 0.631 mmol) in1,2-dichloromethane (3 mL) was added propionaldehyde (36.0 μL). Afterstirring under nitrogen for 15 min, sodium triacetoxyborohydride (161mg, 0.757 mmol) was added. The mixture was stirred overnight. Thereaction was concentrated and purified by silica gel chromatography(95:4.5:1 CHCl₃/methanol/NH₄OH) to yield 162 (80 mg, 31%), and 163 (110mg). For 162: ¹H NMR (300 MHz, CD₃OD) δ 7.79 (s, 1H), 7.54 (d, 2H), 7.33(d, 2H), 7.16 (s, 1H), 6.89 (s, 1H), 4.71 (s, 2H), 4.60 (m, 1H), 3.70(m, 1H), 3.31 (t, 2H), 2.42-2.62 (m, 3H), 2.23 (s, 3H), 1.87-2.10 (m,4H), 1.51 (d, 6H), 1.10-1.33 (m, 4H), 0.94 (t, 3H).

Example 152 Preparation of Compound 162.HCl

[1528] To a stirred solution of 162 (80.0 mg, 0.155 mmol) in ethylacetate (6 mL) was added 2 M HCl in diethyl ether (100 μL). After 20min, the solution was concentrated to afford the HCl salt of 162 inquantitative yield: mp 225-240° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.36 (brs,1H), 7.62 (d, 2H), 7.42 (d, 2H), 7.22 (s, 1H), 6.95 (s, 1H), 4.65-5.05(m, 4H), 3.87 (m, 1H), 3.11 (m, 1H), 2.98 (t, 2H), 2.07-2.36 (m, 5H),1.32-1.85 (m, 14H), 1.04 (t, 3H); API MS m/z=518 [C₂₉H₃₉N₇S+H]⁺.

Example 153 Preparation of Compound 163.HCl

[1529] To a stirred solution of 163 (110 mg, 0.196 mmol) in ethylacetate (8 mL) was added 2 M HCl in diethyl ether (120 μL). After 20min, the solution was concentrated to afford the HCl salt of 163 inquantitative yield: mp 227-229° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.39 (brs,1H), 7.60 (d, 2H), 7.41 (d, 2H), 7.22 (s, 1H), 6.94 (s, 1H), 4.63-5.10(m, 3H), 3.85 (m, 1H), 2.93-3.47 (m, 5H), 1.92-2.40 (m, 7H), 1.32-1.90(m, 14H), 1.04 (t, 6H); API MS m/z=560 [C₃₂H₄₅N₇S+H]⁺.

Example 154 Preparation of Compound 161

[1530] To a 0° C. stirred solution of 160 (100 mg, 0.210 mmol) inmethylene chloride (5 mL) were added pyridine (26.0 μL), aceticanhydride (20.0 μL, 0.210 mmol), and DMAP (3.0 mg, 0.021 mmol). After 40min, the reaction mixture warmed to room temperature. The reactionmixture was concentrated and dried in vacuo. The material was purifiedby silica gel chromatography (90:10:1 CHCl₃/methanol/NH₄OH) to yield161: mp 222-223° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.78 (s, 1H), 7.52 (d,2H), 7.35 (d, 2H), 7.16 (s, 1H), 6.89 (s, 1H), 4.83-5.05 (m, 1H), 4.72(s, 2H), 4.64 (m, 1H), 3.73 (m, 1H), 3.61 (m, 1H), 2.25 (s, 3H),1.97-2.13 (m, 2H), 1.81-1.96 (m, 5H), 1.54 (d, 6H), 1.19-1.40 (m, 4H);API MS m/z=518 [C₂₈H₃₅N₇OS+H]⁺.

Example 155 Preparation of Compound 164

[1531] To a solution of 61 (1.20 g, 2.62 mmol) in ethylene glycoldimethyl ether (75 mL), was added furan-3-boronic acid (0.88 g, 7.85mmol), tris(dibenzylideneacetone)dipalladium(0) (80.0 mg, 0.087 mmol),triphenylphosphine (343 mg, 1.31 mmol), and 2 M sodium carbonatesolution (10 mL). The solution was refluxed under nitrogen overnight.After cooling to room temperature, the reaction mixture was diluted with100 mL water. The aqueous solution was extracted with methylene chloride(3×150 mL). The extracts were combined and washed with water (450 mL)and brine (450 mL). The organic solution was dried over sodium sulfate,filtered, and concentrated. The product was purified by silica gelchromatography (90:10:1 CHCl₃/methanol/NH₄OH) to yield 164 (700 mg,60%).

Example 156 Preparation of Compound 164.HCl

[1532] To a stirred solution of 164 (100 mg, 0.224 mmol) in ethylacetate (6 mL) was added 2 M HCl in diethyl ether (135 μL). After 20min, the solution was concentrated to afford the HCl salt of 164 inquantitative yield: mp 320-330° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.35 (brs,1H), 7.90 (s, 1H), 7.57 (m, 3H), 7.42 (d, 2H), 6.79 (s, 1H), 4.65-5.07(m, 5H), 3.87 (m, 1H), 3.13 (m, 1H), 2.00-2.30 (m, 4H), 1.35-1.75 (m,10H); API MS m/z=446 [C₂₅H₃₁N₇O+H]⁺.

Example 157 Preparation of Compound 166

[1533] To a stirred solution of 164 (200 mg, 0.449 mmol) in1,2-dichloromethane (2 mL) was added propionaldehyde (26.0 μL). Afterstirring under nitrogen for 20 min, sodium triacetoxyborohydride (114mg, 0.539 mmol) was added. The mixture was stirred overnight. Thereaction was concentrated and purified by silica gel chromatography(90:10:1 CHCl₃/methanol/NH₄OH) to yield 166.

Example 158 Preparation of Compound 166.HCl

[1534] To a stirred solution of 166 (120 mg, 0.227 mmol) in ethylacetate (7 mL) was added 2 M HCl in diethyl ether (150 μL). After 20min, the solution was concentrated to afford the HCl salt of 166 inquantitative yield: mp 285-286° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.42 (brs,1H), 7.90 (s, 1H), 7.49-7.62 (m, 3H), 7.43 (d, 2H), 6.80 (s, 1H),4.76-5.10 (m, 3H), 3.91 (m, 1H), 2.93-3.49 (m, 5H), 2.00-2.40 (m, 4H),1.35-1.95 (m, 14H), 1.03 (t, 6H); API MS m/z=530 [C₃₁H₄₃N₇O+H]⁺.

Example 159 Preparation of Compound 165

[1535] To a 0° C. stirred solution of 164 (200 mg, 0.449 mmol) inmethylene chloride (8 mL) was added pyridine (55.0 μL), acetic anhydride(46.0 μL, 0.449 mmol), and DMAP (6.0 mg, 0.045 mmol). After 40 min, thereaction mixture warmed to room temperature. After stirring overnight,the reaction mixture was concentrated and dried in vacuo. The materialwas purified by silica gel chromatography (90:10:1 CHCl₃/methanol/NH₄OH)to yield 165 (190 mg, 87%): mp 241-243° C.; ¹H NMR (300 MHz, CD₃OD) δ7.86 (s, 1H), 7.80 (s, 1H), 7.45-7.54 (m, 3H), 7.32-7.40 (m, 2H), 6.76(s, 1H), 4.71 (s, 2H), 4.62 (m, 1H), 3.74 (m, 1H), 3.61 (m, 1H),1.73-2.11 (m, 7H), 1.54 (d, 6H), 1.20-1.40 (m, 4H); API MS m/z=488[C₂₇H₃₃N₇O₂+H]⁺.

Example 160 Preparation of Compounds 167 and 168

[1536] Compound 75 (0.500 g, 1.10 mmol) was dissolved in1,2-dichloroethane (10 mL). To this stirred solution was addedacetaldehyde (0.054 g, 1.22 mmol) and sodium triacetoxyborohydride(0.360 g, 1.71 mmol). After 1.5 h, the reaction was quenched withsaturated sodium bicarbonate solution (10 mL). The mixture was extractedwith ethyl acetate (10 mL). The organic layers were combined, dried oversodium sulfate, and concentrated. The resulting material was purifiedvia silica gel chromatography (60:1:1 CH₂Cl₂/methanol/triethylamine) toyield 167 (213 mg, 40%), and 168 (109 mg, 19%).

Example 161 Preparation of Compound 167.HCl

[1537] To a stirred solution of 167 (213 mg, 0.440 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (0.264 mL). Theorganic liquid was concentrated to affordthe HCl salt of 167 inquantitative yield: ¹H NMR (300 MHz, CD₃OD) δ 8.30 (brs, 1H), 7.30-7.63(m, 10H), 4.71-4.80 (m, 3H), 3.65-3.72 (m, 1H), 3.48 (q, 2H), 3.10 (brs,2H), 2.10-2.20 (m, 4H), 1.60 (d, 6H), 1.30-1.59 (m, 7H); API MS m/z=484[C₂₉H₃₇N₇+H]⁺.

Example 162 Preparation of Compound 168.HCl

[1538] To a stirred solution of 168 (109 mg, 0.213 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (0.128 mL). Theorganic liquid was concentrated to afford the HCl salt of 168 inquantitative yield: ¹H NMR (300 MHz, CD₃OD) δ 7.25-7.67 (m, 10H),4.60-4.80 (m, 3H), 3.68-3.80 (m, 1H), 3.48 (q, 4H), 2.78-2.95 (m, 4H),2.02-2.17 (m, 2H), 1.10-1.59 (m, 10H), 1.35 (t, 6H); API MS m/z=512[C₃₁H₄₁N₇+H]⁺.

Example 163 Preparation of Compounds 169 and 170

[1539] Compound 75 (0.500 g, 1.10 mmol) was dissolved in1,2-dichloroethane (10 mL). To this stirred solution was addedbutyraldehyde (0.072 g, 1.00 mmol) and sodium triacetoxyborohydride(0.297 g, 1.40 mmol). After 2.5 h, the reaction was quenched withsaturated sodium bicarbonate solution (10 mL). The mixture was extractedwith ethyl acetate (10 mL). The organic layers were combined, dried oversodium sulfate, and concentrated. The resulting material was purifiedvia silica gel chromatography (200:10:1 CH₂Cl₂/methanol/NH₄OH) to yield169 (180 mg, 32%), and 170 (160 mg, 26%).

Example 164 Preparation of Compound 169.HCl

[1540] To a stirred solution of 169 (170 mg, 0.332 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (0.199 mL). Theorganic liquid was concentrated to afford the HCl salt of 169 inquantitative yield: ¹H NMR (300 MHz, CD₃OD) δ 8.30-8.34 (m, 1H),7.30-7.68 (m, 10H), 5.30 (brs, 1H), 4.65-4.90 (m, 4 H), 3.80-3.92 (m,2H), 2.94-3.35 (m, 4H), 2.15-2.32 (m, 4H), 1.41-1.75 (m, 12H), 1.00 (t,3H).

Example 165 Preparation of Compound 171

[1541] To a stirred, 0° C. solution of 169 (125 mg, 0.228 mmol) inmethylene chloride (10 mL), was added pyridine (46 μL), DMAP (6.0 mg,0.046 mmol), and acetic anhydride (24.0 μL, 0.251 mmol). After 1 h undera nitrogen atmosphere, the reaction mixture was warmed to roomtemperature. After stirring overnight, another 2.2 equivalents of aceticanhydride and 0.2 equivalents of DMAP were added and the mixture washeated to reflux. Following concentration, the material was diluted withethyl acetate (20 mL) and saturated sodium bicarbonate solution (20 mL).The organic layer was concentrated and dried in vacuo. The resultingmaterial was purified via silica gel chromatography (90:10:1CH₂Cl₂/methanol/NH₄OH) and trituration with hexanes to yield 171 (26mg): API MS m/z 554 [C₃₃H₄₃N₇O+H]⁺.

Example 166 Preparation of Compound 170.HCl

[1542] To a stirred solution of 170 (150 mg, 0.264 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (0.158 mL). Theorganic liquid was concentrated to afford the HCl salt of 170 inquantitative yield: ¹H NMR (300 MHz, CD₃OD) δ 8.15-8.25 (m, 1H),7.31-7.68 (m, 10H), 4.65-4.90 (m, 3H), 3.70-3.95 (m, 1H), 2.95-3.41 (m,6H), 2.05-2.32 (m, 4H), 1.31-1.79 (m, 18H), 1.00 (t, 6H).

Example 167 Preparation of Compounds 172 and 173

[1543] Compound 75 (0.500 g, 1.10 mmol) was dissolved in1,2-dichloroethane (10 mL). To this stirred solution was addedcyclopropanecarboxaldehyde (0.070 g, 1.00 mmol) and sodiumtriacetoxyborohydride (0.297 g, 1.40 mmol). After 3 h, the reaction wasquenched with saturated sodium bicarbonate solution (10 mL). The mixturewas extracted with ethyl acetate (10 mL). The organic layers werecombined, dried over sodium sulfate, and concentrated. The resultingmaterial was purified via silica gel chromatography (200:10:1CH₂Cl₂/methanol/NH₄OH) to yield 172 (103 mg, 18%), and 173 (160 mg,26%).

Example 168 Preparation of Compound 172.HCl

[1544] To a stirred solution of 172 (103 mg, 0.202 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (0.121 mL). Theorganic liquid was concentrated to afford the HCl salt of 172 inquantitative yield: ¹H NMR (300 MHz, CD₃OD) δ 8.30 (brs, 1H), 7.30-7.69(m, 10H), 4.69-4.92 (m, 4H), 3.80-3.92 (m, 1H), 2.84-3.19 (m, 3H),2.11-2.28 (m, 4H), 1.37-1.72 (m, 10H), 1.05-1.15 (m, 1H), 0.68-0.74 (m,2H), 0.38-0.42 (m, 2H).

Example 169 Preparation of Compound 173.HCl

[1545] To a stirred solution of 173 (160 mg, 0.284 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (0.170 mL). Theorganic liquid was concentrated to afford the HCl salt of 173 inquantitative yield: ¹H NMR (300 MHz, CD₃OD) δ 8.30-8.41 (m, 1H),7.30-7.68 (m, 10H), 5.30 (brs, 1H), 4.68-4.90 (m, 4H), 3.55-3.95 (m,2H), 3.05-3.20 (m, 4H), 2.00-2.32 (m, 4H), 1.10-1.90 (m, 10H), 0.75-0.80(m, 4H), 0.35-0.50 (m, 4H).

Example 170 Preparation of Compounds 174 and 175

[1546] Compound 75 (1.50 g, 3.29 mmol) was dissolved in1,2-dichloroethane (30 mL). To this stirred solution was addedpropionaldehyde (0.174 g, 2.99 mmol) and sodium triacetoxyborohydride(0.888 g, 4.19 mmol). After 1.5 h, the reaction was quenched withsaturated sodium bicarbonate solution (30 mL). The mixture was extractedwith ethyl acetate (30 mL). The organic layers were combined, dried oversodium sulfate, and concentrated. The resulting material was purifiedvia silica gel chromatography (200:10:1 CH₂Cl₂/methanol/NH₄OH) to yield174 (317 mg, 19%):

[1547]¹H NMR (300 MHz, CD₃OD) δ 7.26-7.80 (m, 10H), 4.62-4.81 (m, 3H),3.74 (brs, 1H), 2.41-2.62 (m, 3H), 1.90-2.11 (m, 4H), 1.52 (d, 6H),1.12-1.52 (m, 8H), 0.92 (t, 3H), and 175 (320 mg, 18%): ¹H NMR (300 MHz,CD₃OD) δ 8.18-8.28 (m, 1H), 7.28-7.68 (m, 10H), 4.65-4.90 (m, 3H),3.81-3.94 (m, 1H), 2.94-3.25 (m, 4H), 2.02-2.31 (m, 6H), 1.40-1.81 (m,14H), 1.05 (t, 6H).

Example 171 Preparation of Compound 267

[1548] The HCl salt of 167 (10 mg, 0.037 mmol), was dispersed in ethylacetate and neutralized with sodium bicarbonate. The organic materialwas dried over magnesium sulfate and concentrated. The solid wasdissolved in dry CH₂Cl₂ (10 mL) and cooled to 0° C. To the solution wasadded DMAP (9 mg), pyridine (0.074 mL) and acetic anhydride (0.037 mL).The ice bath was removed after 1 h. After being stirred overnight,additional DMAP and Ac₂O was added in portions to consume startingmaterial by TLC analysis. The mixture was heated to reflux for 2 d. Uponcooling, the mixture was concentrated in vacuo, then neutralized withaqueous sodium bicarbonate, extracted with ethyl acetate, dried andconcentrated. The residue was purified by chromatography to provide 267:API MS m/z 526 [C₃₁H₃₉N₇O+H]⁺.

Example 172 Preparation of Compound 177

[1549] To a solution of 61 (1.00 g, 2.21 mmol) and 3-tolylboronic acid(0.33 g, 2.43 mmol) in tetrahydrofuran (5 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (0.010 g, 0.011 mmol),tri-tert-butylphosphine (5.5 mg, 0.027 mmol), and potassium fluoride(0.42 g, 7.29 mmol). After mixing overnight at room temperature, thereaction mixture was refluxed for 24 h and cooled to room temperature.The reaction mixture was diluted with ether (50 mL) and filtered throughCelite. The organic liquid was concentrated and the resulting materialwas purified via silica gel chromatography (90:10:1CH₂Cl₂/methanol/NH₄OH) to yield 177 (0.70 g, 71%).

Example 173 Preparation of Compound 177.HCl

[1550] To a stirred solution of 177 (449 mg, 0.956 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (575 μL). The organicliquid was concentrated to afford the HCl salt of 177 in quantitativeyield: mp 186-195° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.82 (s, 1H), 7.54 (d,2H), 7.20-7.48 (m, 5H), 7.12 (d, 1H), 4.83-5.10 (m, 2H), 4.77 (s, 2H),4.64 (m, 1H), 3.77 (m, 1H), 3.03 (m, 1H), 2.38 (s, 3H), 1.93-2.20 (m,4H), 1.19-1.70 (m, 10H); API MS m/z=470 [C₂₈H₃₅N₇+H]⁺.

Example 174 Preparation of Compound 178

[1551] To a stirred solution of 177 (219 mg, 0.466 mmol) in methylenechloride (25 mL) was added acetic anhydride (48 μL, 0.513 mmol), DMAP(5.7 mg, 0.047 mmol), and pyridine (57.0 μL, 0.699 mmol). The mixturewas placed under a nitrogen atmosphere and immersed in an ice waterbath. After 30 min, the reaction mixture was warmed to room temperatureand stirred for another 1.5 h. The solution was concentrated and theresulting material was purified via silica gel chromatography (95:5:1CH₂Cl₂/methanol/NH₄OH) to afford 178.

Example 175 Preparation of Compound 178.HCl

[1552] To a stirred solution of 178 (50.0 mg, 0.098 mmol) in ethylacetate (5 mL) was added 2 M HCl in diethyl ether (59.0 μL). The organicliquid was concentrated to afford the HCl salt of 178 in quantitativeyield: mp 165-174° C.; ¹H NMR (300 MHz, CD₃OD) δ 8.26 (brs, 1H), 7.61(d, 2H), 7.47 (d, 2H), 7.24-7.41 (m, 3H), 7.15 (d, 1H), 4.62-5.08 (m,4H), 3.83 (m, 1H), 3.67 (m, 1H), 2.39 (s, 3H), 1.87-2.20 (m, 7H), 1.60(d, 6H), 1.40 (m, 4H); API MS m/z=512 [C₃₀H₃₇N₇O+H]⁺.

Example 176 Preparation of Compound 179

[1553] To a solution of 61 (2.00 g, 4.36 mmol) and 3-methoxyphenylboronic acid (0.73 g, 4.79 mmol) in tetrahydrofuran (10 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.022 mmol),tri-tert-butylphosphine (10.0 mg, 0.052 mmol), and potassium fluoride(0.84 g, 14.39 mmol). After refluxing overnight, the reaction mixturewas diluted with ether (50 mL) and filtered through Celite. The organicliquid was concentrated and the resulting material was purified viasilica gel chromatography (95:5:1 CH₂Cl₂/methanol/NH₄OH) to yield 179(1.18 g, 56%).

Example 177 Preparation of Compound 179.HCl

[1554] To a stirred solution of 179 (980 mg, 2.02 mmol) in ethyl acetate(10 mL) was added 2 M HCl in diethyl ether (1.21 mL). The organic liquidwas concentrated to afford the HCl salt of 179 in quantitative yield: mp182-189° C.; ¹H NMR (300 MHz, CD₃OD) δ 7.80 (s, 1H), 7.54 (d, 2H), 7.40(d, 2H), 7.30 (t, 1H), 7.12 (m, 2H), 6.87 (m, 1H), 4.76 (s, 2H), 4.62(m, 1H), 3.67-3.90 (m, 4H), 2.94 (m, 1H), 1.90-2.20 (m, 4H), 1.17-1.65(m, 1O H); API MS m/z=486 [C₂₈H₃₅N₇O+H]⁺.

Example 178 Preparation of Compound 180

[1555] To a stirred solution of 179 (200 mg, 0.412 mmol) in methylenechloride (25 mL) was added acetic anhydride (43 μL, 0.450 mmol), DMAP(5.0 mg, 0.041 mmol), and pyridine (50.0 μL, 0.618 mmol). The mixturewas placed under a nitrogen atmosphere and immersed in an ice waterbath. After 30 min, the reaction mixture was warmed to room temperatureand stirred for another 1.5 h. The solution was concentrated and theresulting material was purified via silica gel chromatography (95:5:1CH₂Cl₂/methanol/NH₄OH) to afford 180.

Example 179 Preparation of Compound 180.HCl

[1556] To a stirred solution of 180 (60.0 mg, 0.114 mmol) in ethylacetate (5 mL) was added 2 M HCl in diethyl ether (68.0 μL). The organicliquid was concentrated to afford the HCl salt of 180 in quantitativeyield: ¹H NMR (300 MHz, CD₃OD) δ 8.20 (brs, 1H), 7.62 (d, 2H), 7.46 (d,2H), 7.34 (t, 1H), 7.10-7.20 (m, 2H), 6.90 (1H), 4.60-5.10 (m, 4H), 3.83(s, 3H), 3.64 (m, 1H), 3.20-3.42 (m, 1H), 1.87-2.18 (m, 7H), 1.60 (d,6H), 1.22-1.50 (m, 4H); API MS m/z=528 [C₃₀H₃₇N₇O₂+H]⁺.

Example 180 Preparation of Compound 181

[1557] To a solution of 61 (2.00 g, 4.36 mmol) and furan-2-boronic acid(1.50 g, 13.1 mmol) in ethylene glycol dimethyl ether (150 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (120 mg, 0.130 mmol),tri-tert-butylphosphine (570 mg, 2.18 mmol), and 2 M sodium carbonatesolution (12.5 mL, 25.3 mmol). After refluxing overnight, 2 moreequivalents of furan-2-boronic acid were added. The reaction wasrefluxed for 24 h, cooled to room temperature, and diluted with water(50 mL). The aqueous mixture was extracted with methylene chloride (3×80mL). The extracts were combined and washed with water (250 mL) and brine(250 mL). The organic phase was dried over sodium sulfate and filtered.The organic liquid was concentrated and the resulting material waspurified via silica gel chromatography (95:5:1 CH₂Cl₂/methanol/NH₄OH) toyield 181.

Example 181 Preparation of Compound 181.HCl

[1558] To a stirred solution of 181 (600 mg, 1.35 mmol) in ethyl acetate(10 mL) was added 2 M HCl in diethyl ether (0.810 mL). The organicliquid was concentrated to afford the HCl salt of 181 (406 mg, 68%): ¹HNMR (300 MHz, CD₃OD) δ 8.06 (s, 1H), 7.66 (d, 2H), 7.53 (s, 1H), 7.41(d, 2H), 6.74 (m, 1H), 6.49 (m, 1H), 4.60-5.00 (m, 5H), 3.82 (m, 1H),3.10 (m, 1H), 1.95-2.20 (m, 4H), 1.20-1.61 (m, 10H); API MS m/z 446[C₂₅H₃₁N₇O+H]⁺.

Example 182 Preparation of Compound 182

[1559] To a stirred solution of 181 (750 mg, 1.68 mmol) in methylenechloride (30 mL) was added acetic anhydride (0.18 mL, 1.85 mmol), DMAP(20.8 mg, 0.1 7 mmol), and pyridine (0.20 mL, 2.52 mmol). The mixturewas placed under a nitrogen atmosphere and immersed in an ice waterbath. After 30 min, the reaction mixture was warmed to room temperatureand stirred for another 1.5 h. The solution was concentrated and theresulting material was purified via silica gel chromatography (95:5:1CH₂Cl₂/methanol/NH₄OH) to afford 182 (530 mg, 65%).

Example 183 Preparation of Compound 182.HCl

[1560] To a stirred solution of 182 (300 mg, 0.620 mmol) in ethylacetate (10 mL) was added 2 M HCl in diethyl ether (0.370 mL). Theorganic liquid was concentrated to afford the HCl salt of 182 inquantitative yield: ¹H NMR (300 MHz, CD₃OD) δ 8.25 (brs, 1H), 7.56-7.73(m, 2H), 7.54 (s, 1H), 7.30-7.47 (m, 2H), 6.75 (m, 1H), 6.49 (m, 1H),4.60-5.05 (m, 4H), 3.73-3.90 (m, 1H), 3.55-3.73 (m, 1H), 1.82-2.23 (m,7H), 1.15-1.70 (m, 10H); API MS m/z=488 [C₂₇H₃₃N₇O₂+H]⁺.

Example 184 Preparation of Compound 183

[1561] To a stirred mixture of 6-chloronicotinamide (5.00 g, 31.9 mmol)in ethanol (13 mL) and toluene (80 mL) was added 3-fluorobenzeneboronicacid (4.92 g, 35.1 mmol) and 2 M sodium carbonate solution (32 mL). Thesuspension was heated to 80° C. and degassed with argon for 1 h. Aftercooling to room temperature, tetrakis(triphenylphophine)palladium(0)(1.11 g, 0.958 mmol) was added. The reaction mixture was refluxed underargon for 3 h. After cooling to room temperature, the mixture wasdiluted with water (100 mL) and filtered. The filter cake was washedwith water and dried in vacuo to afford 183 (6.38 g, 92%).

Example 185 Preparation of Compound 184

[1562] To a stirred suspension of 183 (3.00 g, 13.9 mmol) intetrahydrofuran (25 mL) was added dropwise 1 M borane in THF (97.0 mL,97.0 mmol). After refluxing for 2 h, the reaction mixture was cooled inan ice bath. The mixture was acidified to pH 1 with 2 N HCl and stirredfor 1 h. The pH was raised to a value of 10 by adding 6 N NaOH and theresulting solution was extracted with ethyl acetate (3×50 mL). Theextractions were combined, washed with brine (150 mL), and dried oversodium sulfate. The suspension was filtered and concentrated. Theresulting material was purified by precipitation as the HCl salt from anethanol solution. The product was recovered by filtration and dried invacuo to yield 184 (1.69 g, 51%): ¹H NMR (300 MHz, CD₃OD) δ 8.92 (s,1H), 8.41 (d, 1H), 8.27 (d, 1H), 7.77-7.90 (m, 2H), 7.35-7.70 (m, 2H),4.36 (s, 2H).

Example 186 Preparation of Compound 185

[1563] The amine 184 (1.84 g, 7.69 mmol), 2,6-dichloropurine (1.31 g,6.99 mmol), and N,N-diisopropylethylamine (2.68 mL, 15.4 mmol) weredissolved in ethanol (65 mL). After refluxing overnight, the solutionwas immersed in an ice water bath for 20 min. The mixture was filteredand cake was washed with water. The cake was triturated with ethanol anddiethyl ether and dried in vacuo to afford 185 (1.12 g, 47%).

Example 187 Preparation of Compound 186

[1564] To a stirred solution of 185 (1.00 g, 2.94 mmol) indimethylsulfoxide (100 mL) was added potassium carbonate (2.19 g, 15.9mmol) and 2-iodopropane (0.88 mL, 8.81 mmol). The mixture was placedunder an argon atmosphere and stirred overnight. The reaction mixturewas poured into stirred water (300 mL) and the resulting solution wasextracted with ethyl acetate (3×300 mL). The extractions were combined,washed with water (900 mL) and brine (900 mL), and dried over magnesiumsulfate. Following filtration, the organic liquid was concentrated. Thematerial was purified by recrystallization from ethyl acetate in hexanesto yield 186 (0.92 g, 82%).

Example 188 Preparation of Compound 187

[1565] In a sealed tube were combined 186 (640 mg, 1.67 mmol),trans-1,4-diaminocyclohexane (0.96 g, 8.36 mmol), and ethanol (3.5 mL).The reaction mixture was heated to 150° C. for 4 d and cooled to roomtemperature. The solution was poured into stirred ice water (5 mL) andthe resulting mixture was extracted with methylene chloride (3×5 mL).The extractions were combined, washed with water (15 mL) and brine (15mL), and dried over sodium sulfate. The organic liquid was concentrated.Purification by column chromatography (97:3 CH₂Cl₂/methanol) andtrituration with hexanes yielded the free base, 187: ¹H NMR (300 MHz,CDCl₃) δ 8.68 (s, 1H), 7.60-7.82 (m, 4H), 7.50 (s, 1H), 7.42 (q, 1H),7.11 (m, 1H), 6.07 (m, 1H), 4.85 (d, 2H), 4.60 (m, 2H), 3.74 (m, 1H),2.69 (m, 1H), 2.02-2.19 (m, 2H), 1.78-1.96 (m, 2H), 1.52 (d, 6H),1.10-1.36 (m, 4H); API MS m/z=475 [C₂₆H₃₁FN₈+H]⁺.

Example 189 Preparation of Compound 188

[1566] The free amine 187 (80.0 mg, 0.170 mmol) was dissolved inmethylene chloride (4 mL). The solution was immersed in an ice waterbath and acetic anhydride (17.5 μL, 0.185 mmol), DMAP (2.0 mg, 0.017mmol), and pyridine (20.0 μL, 0.252 mmol) were added. After stirring for30 min, the solution was warmed to room temperature and concentrated.Purification via silica gel chromatography and trituration with hexanesyielded 188 (67 mg, 78%): mp 199-230° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.71(s, 1H), 7.62-7.85 (m, 4H), 7.52 (s, 1H), 7.42 (m, 1H), 7.10 (m, 1H),6.01 (m, 1H), 5.28 (d, 1H), 4.81 (d, 2H), 4.62 (m, 2H), 3.72 (m, 2H),1.90-2.27 (m, 7H), 1.53 (d, 6H), 1.24 (m, 4H); API MS m/z=517[C₂₈H₃₃FN₈O+H]

Example 190 Preparation of Compound 189

[1567] To a stirred mixture of 6-chloronicotinamide (3.00 g, 19.2 mmol)in ethanol (7.6 mL) and toluene (48 mL) were added3-methoxyphenylboronic acid (3.20 g, 21.1 mmol) and 2 M sodium carbonatesolution (19 mL). The suspension was heated to 80° C. and degassed withargon for 1 h. After cooling to room temperature,tetrakis(triphenylphophine)palladium(0) (664 mg, 0.575 mmol) was added.The reaction mixture was refluxed under argon for 3 h. After cooling toroom temperature, the mixture was diluted with water (100 mL) andfiltered. The filter cake was washed with water and dried in vacuo toafford 189 (3.62 g, 83%).

Example 191 Preparation of Compound 190

[1568] To a stirred solution of 189 (3.00 g, 13.1 mmol) intetrahydrofuran (25 mL) was added dropwise 1 M borane in THF (92.0 mL,92.0 mmol). After refluxing for 4 h, the reaction mixture was cooled inan ice bath. The mixture was acidified to pH 1 with 2 N HCl and stirredfor 1 h. The pH was raised to a value of 10 by adding 6 N NaOH and theresulting solution was extracted with ethyl acetate (3×50 mL). Theextractions were combined, washed with brine (150 mL), and dried oversodium sulfate. The suspension was filtered and concentrated. Theresulting material was purified by precipitation as the HCl salt from anethanol solution. The product was recovered by filtration and dried invacuo to yield 190 (1.81 g, 55%).

Example 192 Preparation of Compound 191

[1569] The amine 190 (1.80 g, 7.18 mmol), 2,6-dichloropurine (1.22 g,6.53 mmol), and N,N-diisopropylethylamine (1.86 g, 6.53 mmol) weredissolved in ethanol (82 mL). After refluxing overnight, the dispersionwas immersed in an ice water bath for 60 min. The mixture was filteredand cake was washed with water. The cake was triturated with ethanol anddiethyl ether and dried in vacuo to afford 191 (1.04 g, 44%).

Example 193 Preparation of Compound 192

[1570] To a stirred solution of 191 (1.04 g, 2.84 mmol) indimethylsulfoxide (60 mL) was added potassium carbonate (2.12 g, 15.3mmol) and 2-iodopropane (0.85 mL, 8.52 mmol). The mixture was placedunder an argon atmosphere and stirred overnight. The reaction mixturewas poured into stirred water (60 mL) and the resulting solution wasextracted with ethyl acetate (3×60 mL). The extractions were combined,washed with water (180 mL) and brine (180 mL), and dried over magnesiumsulfate. Following filtration, the organic liquid was concentrated. Thematerial was purified by recrystallization from ethyl acetate in hexanes(1:40) to yield 192.

Example 194 Preparation of Compound 193

[1571] In a sealed tube were combined 192 (400 mg, 1.09 mmol),trans-1,4-diaminocyclohexane (1.25 g, 10.9 mmol), and ethanol (4.0 mL).The reaction mixture was heated to 150° C. for 24 h and cooled to roomtemperature. The solution was filtered and the filtrate wasconcentrated. Purification by column chromatography (97:3CH₂Cl₂/methanol) yielded the free base, 193 (240 mg, 45%).

Example 195 Preparation of Compound 194

[1572] The free amine 193 (130 mg, 0.27 mmol) was dissolved in methylenechloride (6 mL). The solution was immersed in an ice water bath andacetic anhydride (28.0 μL, 0.294 mmol), DMAP (3.2 mg, 0.026 mmol), andpyridine (33.0 μL, 0.401 mmol) were added. After stirring for 30 min,the solution was warmed to room temperature and concentrated.Purification via prep-TLC (9:1 CH₂Cl₂/methanol) and trituration withethyl acetate yielded 194: mp 161-163° C.; ¹H NMR (300 MHz, CDCl₃) δ8.76 (s, 1H), 7.77 (d, 1H), 7.64 (d, 1H), 7.50 (m, 3H), 7.35 (t, 1H),6.73-7.00 (m, 2H), 5.33 (d, 1H), 4.50-4.92 (m, 4H), 3.56-4.00 (m, 5H),1.84-2.22 (m, 7H), 1.55 (d, 6H), 1.25 (m, 4H); API MS m/z=529[C₂₉H₃₆N₈O₂+H]⁺.

Example 196 Preparation of Compound 195

[1573] To a stirred mixture of 6-chloronicotinamide (2.00 g, 12.8 mmol)in ethanol (5.0 mL) and toluene (32 mL) was added thiophene-2-boronicacid (1.80 g, 14.1 mmol) and 2 M sodium carbonate solution (13 mL). Thesuspension was heated to 80° C. and degassed with argon for 1 h. Aftercooling to room temperature, tetrakis(triphenylphophine)palladium(0)(443 mg, 0.383 mmol) was added. The reaction mixture was refluxed underargon for 3 h. After cooling to room temperature, another 0.950 gthiophene-2-boronic acid and 280 mgtetrakis(triphenylphophine)palladium(0) were added to the reactionmixture. It was refluxed for 4 h and cooled to room temperature. Themixture was diluted with water (50 mL) and filtered. The filter cake waswashed with water and dried in vacuo to afford 195 (1.65 g, 63%).

Example 197 Preparation of Compound 196

[1574] To a stirred solution of 195 (1.40 g, 6.86 mmol) intetrahydrofuran (23 mL) was added dropwise 1 M borane in THF (48.0 mL,48.0 mmol). After refluxing for 1 h, the reaction mixture was cooled inan ice bath. The mixture was acidified to pH 1 with 2 N HCl and stirredfor 1 h. The pH was raised to a value of 10 by adding 6 N NaOH and theresulting solution was extracted with ethyl acetate (3×50 mL). Theextractions were combined, washed with brine (150 mL), and dried oversodium sulfate. The suspension was filtered and concentrated. Theresulting material was purified by precipitation as the HCl salt from anethanol solution. The product was recovered by filtration and dried invacuo to yield 196 (0.87 g, 56%).

Example 198 Preparation of Compound 197

[1575] The amine 196 (210 mg, 1.10 mmol), 2,6-dichloropurine (188 mg,1.00 mmol), and N,N-diisopropylethylamine (286 g, 2.21 mmol) weredissolved in ethanol (12 mL). After refluxing overnight, the suspensionwas immersed in an ice water bath for 60 min. The mixture was filteredand cake was washed with water. The cake was triturated with ethanol anddiethyl ether and dried in vacuo to afford 197 (206 mg, 60%).

Example 199 Preparation of Compound 198

[1576] To a stirred solution of 197 (200 mg, 0.583 mmol) indimethylsulfoxide (12 mL) was added potassium carbonate (435 mg, 3.15mmol) and 2-iodopropane (0.18 mL, 1.75 mmol). The mixture was placedunder an argon atmosphere and stirred overnight. The reaction mixturewas poured into stirred water (15 mL) and the resulting solution wasextracted with ethyl acetate (3×30 mL). The extractions were combined,washed with water (90 mL) and brine (90 mL), and dried over magnesiumsulfate. Following filtration, the organic liquid was concentrated to 10yield 198 (200 mg, 89%).

Example 200 Preparation of Compound 199

[1577] In a sealed tube were combined 198 (100 mg, 0.260 mmol),trans-1,4-diaminocyclohexane (297 mg, 2.60 mmol), and ethanol (2.0 mL).The reaction mixture was heated to 150° C. for 2 d and cooled to roomtemperature. The solution was filtered and diluted with ethanol. Thefiltrate was concentrated, and converted to its HCl salt to afford 199:¹H NMR (300 MHz, CD₃OD) δ 9.00 (s, 1H), 8.72 (d, 2H), 8.46 (d, 1H), 8.27(m, 1H), 8.15 (d, 1H), 7.54 (m, 1H), 4.89-5.35 (3H), 4.04 (m, 1H), 3.35(m, 1H), 2.20-2.50 (m, 4H), 1.55-1.90 (m, 10H); ESI MS m/z=463[C₂₄H₃₀N₈S+H]⁺.

Example 201 Preparation of Compound 200

[1578] The free amine 199 (100 mg, 0.216 mmol) was dissolved inmethylene chloride (5 mL). The solution was immersed in an ice waterbath and acetic anhydride (20.0 1L, 0.216 mmol), DMAP (2.6 mg, 0.021mmol), and pyridine (33.0 μL, 0.324 mmol) were added. After stirring for30 min, the solution was warmed to room temperature and concentrated.Purification via prep-TLC (10:1 CH₂Cl₂/methanol) yielded 200 (20 mg): mp206-208° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 7.70 (d, 1H), 7.58(d, 1H), 7.53 (m, 2H), 7.37 (m, 1H), 7.10 (m, 1H), 6.15 (brs, 1H), 5.33(d, 1H), 4.76 (d, 2H), 4.61 (m, 2H), 3.70 (m, 2H), 1.75-2.15 (m, 7H),1.52 (d, 6H), 1.23 (m, 4H); API MS m/z=505 [C₂₆H₃₂N₈OS+H]⁺.

Example 202 Preparation of Compound 201

[1579] To a stirred solution of 6-chloronicotinamide (2.80 g, 17.9 mmol)in ethanol (7.5 mL) and toluene (48 mL) was added furan-2-boronic acid(3.00 g, 26.8 mmol) and 2 M sodium carbonate solution (18 mL). Thesuspension was heated to 80° C. and degassed with argon for 1 h. Aftercooling to room temperature, tetrakis(triphenylphophine)palladium(0)(619 mg, 0.536 mmol) was added. The reaction mixture was refluxed underargon for 2 d then cooled to room temperature. The mixture was dilutedwith water (75 mL) and filtered. The filter cake was washed with waterand dried in vacuo to afford 201 (1.95 g, 58%).

Example 203 Preparation of Compound 202

[1580] To a stirred solution of 201 (1.69 g, 8.98 mmol) intetrahydrofuran (34 mL) was added dropwise 1 M borane in THF (50.0 mL,50.0 mmol). After refluxing for 2 h, the reaction mixture was cooled inan ice bath. The mixture was acidified to pH 1 with 2 N HCl and stirredfor 1 h. The pH was raised to a value of 10 by adding 6 N NaOH and theresulting solution was extracted with ethyl acetate (3×50 mL). Theextractions were combined, washed with brine (150 mL), and dried oversodium sulfate. The suspension was filtered and concentrated. Theresulting material was purified by precipitation as the HCl salt from anethanol solution. The product was recovered by filtration and dried invacuo to yield 202 (1.12 g, 50%).

Example 204 Preparation of Compound 203

[1581] The amine 202 (177 mg, 1.02 mmol), 2,6-dichloropurine (173 mg,0.920 mmol), and N,N-diisopropylethylamine (267 g, 2.07 mmol) weredissolved in ethanol (11 mL). After refluxing overnight, the suspensionwas immersed in an ice water bath for 60 min. The mixture was filteredand cake was washed with water. The cake was triturated with ethanol anddiethyl ether and dried in vacuo to afford 203 (166 mg, 54%).

Example 205 Preparation of Compound 204

[1582] To a stirred solution of 203 (166 mg, 0.508 mmol) indimethylsulfoxide (11 mL) was added potassium carbonate (379 mg, 2.74mmol) and 2-iodopropane (0.150 mL, 1.52 mmol). The mixture was placedunder an argon atmosphere and stirred overnight. The reaction mixturewas poured into stirred water (15 mL) and the resulting solution wasextracted with ethyl acetate (3×30 mL). The extractions were combined,washed with water (90 mL) and brine (90 mL), and dried over magnesiumsulfate. Following filtration, the organic liquid was concentrated toyield 204 (178 mg, 95%).

Example 206 Preparation of Compound 205

[1583] In a sealed tube were combined 204 (170 mg, 0.461 mmol),trans-1,4-diaminocyclohexane (526 mg, 4.61 mmol), and ethanol (2.5 mL).The reaction mixture was heated to 150° C. for 4 d and cooled to roomtemperature. The solution was filtered and concentrated to afford 205.

Example 207 Preparation of Compound 206

[1584] The free amine 205 (100 mg, 0.224 mmol) was dissolved inmethylene chloride (5 mL). The solution was immersed in an ice waterbath and acetic anhydride (21.0 μL, 0.224 mmol), DMAP (2.7 mg, 0.022mmol), and pyridine (34.0 μL, 0.336 mmol) were added. After stirring for30 min, the solution was stored at 0° C. overnight. Purification viaprep-TLC (9:1 CH₂Cl₂/methanol) yielded 206 (43 mg): mp 216-218° C.; ¹HNMR (300 MHz, CDCl₃) δ 8.63 (s, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.50(m, 2H), 6.99 (m, 1H), 6.50 (m, 1H), 6.15 (brs, 1H), 5.36 (d, 1H), 4.79(d, 2H), 4.62 (m, 2H), 3.68 (m, 2H), 1.78-2.20 (m, 7H), 1.54 (d, 6H),1.22 (m, 4H); API MS m/z=489 [C₂₆H₃₂N₈O₂+H]⁺.

Example 208 Preparation of Compound 207

[1585] Prepared by reaction of 72 with ethylene diamine by generalmethods described above (91%): ¹H NMR (300 MHz, (CD₃)₂SO) δ 8.06 (brs,3H), 7.65 (d, 4 H), 7.31-7.52 (m, 6H), 4.68-4.90 (m, 3H), 3.61 (m, 2H),3.01 (m, 2H), 1.54 (d, 6H); ESI MS m/z=402 [C₂₃H₂₇N₇+H]⁺.

Example 209 Preparation of Compound 208

[1586] Prepared by reaction of 207 under standard acetylation conditions(35%): ¹H NMR (300 MHz, CDCl₃) δ 7.49-7.62 (m, 5H), 7.30-7.48 (m, 5H),6.44 (brs, 1H), 6.13 (brs, 1H), 5.05 (t, 1H), 4.82 (d, 2H), 4.65 (m,1H), 3.58 (m, 2H), 3.45 (m, 2H), 1.87 (s, 3H), 1.54 (d, 6H); ESI MSm/z=444 [C₂₅H₂₉N₇O+H]⁺.

Example 210 Preparation of Compound 211

[1587] Prepared by reaction of 72 and 1,3-propanediamine (28%): ¹H NMR(300 MHz, (CD₃)₂SO) δ 8.00-8.22 (m, 3H), 7.63-7.70 (d, 4H), 7.32-7.59(m, 6H), 4.84 (m, 2H), 4.70 (m, 1H), 4.43 (m, 2H), 2.88 (m, 2H), 1.88(m, 2H), 1.52 (d, 6H); ESI MS m/z=416 [C₂₄H₂₉N₇+H]⁺.

Example 211 Preparation of Compound 212

[1588] Prepared by reaction of 211 with acetic anhydride under standardconditions (44%): mp 106-107° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.62(m, 5H), 7.28-7.50 (m, 5H), 5.87 (brs, 2H), 4.93 (m, 1H), 4.84 (m, 2H),4.66 (m, 1H), 3.49 (m, 2H), 3.33 (m, 2H), 1.91 (s, 3H), 1.74 (m, 2H),1.55 (d, 6H); ESI MS m/z=458 [C₂₆H₃ ₁N₇O+H]⁺.

Example 212 Preparation of Compound 213

[1589] Prepared by the general methods described above (48%): ¹H NMR(300 MHz, CDCl₃) δ 7.29-7.66 (m, 10H), 6.40 (brs, 1H), 4.71-5.03 (m,3H), 4.61 (m, 1H), 3.30-3.55 (m, 2H), 2.73 (m, 2H), 2.32 (m, 2H),1.38-1.85 (m, 10H); ESI MS m/z=430 [C₂₅H₃₁N₇+H]⁺.

Example 213 Preparation of Compound 214

[1590] Prepared by the general methods described above (45%): ¹H NMR(300 MHz, CDCl₃) δ 7.27-7.65 (m, 10H), 5.92 (m, 1H), 5.43 (m, 1H), 4.83(m, 3 H), 4.66 (m, 1H), 3.46 (m, 2H), 3.25 (m, 2H), 1.93 (s, 3H), 1.76(m, 3H), 1.40-1.70 (m, 8H); ESI MS m/z=472 [C₂₇H₃₃N₇O+H]⁺.

Example 214 Preparation of Compounds 209 and 210

[1591] Prepared by the general methods described above. For 210 (17%):¹H NMR (300 MHz, (CD₃)₂SO) δ 7.31-7.72 (m, 10H), 4.64-4.92 (m, 3H), 3.73(m, 4H), 2.84-3.33 (m, 6H), 1.43-1.79 (m, 10H), 0.85 (m, 6H); ESI MSm/z=486 [C₂₉H₃₉N₇+H]⁺. For 209: ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.63 (m,10H), 6.46 (brs, 1H), 5.83 (brs, 1H), 4.85 (m, 2H), 4.66 (m, 1H), 3.79(d, 2H), 3.11 (m, 2H), 2.76 (m, 2H), 1.76 (m,2H), 1.50 (d, 6H), 0.84 (m,3H); ESI MS m/z=444 [C₂₆H₃₃N₇+H]⁺.

Example 215 Preparation of Compound 215

[1592] Prepared by the general methods described above: ¹H NMR (300 MHz,CDCl₃) δ 7.22-7.60 (m, 10H), 6.18 (brs, 1H), 5.11 (brs, 1H), 4.81 (m,2H), 4.64 (m, 1H), 3.40 (m, 2H), 2.87 (m, 2H), 2.77 (m, 2H), 1.70-2.00(m, 4H), 1.55-1.70 (m, 2H), 1.51 (m, 6H), 0.92 (t, 3H); ESI MS m/z 472[C₂₈H₃₇N₇+H]⁺.

Example 216 Preparation of Compound 216

[1593] Prepared by the general methods described above (71%): ¹H NMR(300 MHz, CDCl₃) δ 7.28-7.61 (m, 10H), 6.01 (brs, 1H), 4.86 (d, 2H),4.66 (m, 1H), 3.79-3.89 (m, 1H), 3.70-3.79 (m, 1H), 3.57-3.70 (m, 2H),3.27-3.37 (m, 1H), 2.10-2.23 (m, 1H), 1.68-1.82 (m, 1H), 1.55 (d, 6H);ESI MS m/z=428 [C₂₅H₂₉N₇+H]⁺.

Example 217 Preparation of Compound 217

[1594] Prepared by the general methods described above: TLC silica gelR_(f)=0.52 (20:1:0.01-CH₂Cl₂/MeOH/NH₄OH).

Example 218 Preparation of Compound 218

[1595] Prepared by the general methods described above: ¹H NMR (300 MHz,(CD₃)₂SO) δ 8.02 (brs, 1H), 7.88 (s, 1H), 7.54-7.68 (m, 4H), 7.40-7.50(m, 3H), 7.30-7.40 (m, 1H), 7.26 (s, 1H), 6.77 (s, 1H), 4.50-4.72 (m,4H), 2.78 (t, 2H), 2.31 (m, 1H), 1.68 (d, 2H), 1.49 (d, 6H); ESI MSm/z=470 [C₂₇H₃N₇O+H]⁺.

Example 219 Preparation of Compound 219

[1596] Prepared by the general methods described above (66%): ¹H NMR(300 MHz, CDCl₃) δ 7.28-7.62 (m, 10H), 5.89 (brs, 1H), 4.86 (d, 4H),4.67 (m, 1H), 2.81 (t, 2H), 2.58 (d, 2H), 1.77 (d, 2H), 1.40-1.69 (m,10H), 1.06-1.31 (m, 2H); ESI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 220 Preparation of Compound 221

[1597] The compound 220 (100 mg, 0.170 mmol) was dissolved in methanol(25 mL). To the stirred solution was added ammonium formate (100 mg),and Pd/C (10.0 mg). After refluxing for 2 h, more ammonium formate (100mg) and Pd/C (10.0 mg) were added. The reaction was cooled to roomtemperature and filtered through Celite. The filtrate was concentratedin vacuo. The resulting material was purified via silica gelchromatography (3:1:0.01 CH₂Cl₂/MeOH/NH₄OH) to yield 221 (26.9 mg, 34%):¹H NMR (300 MHz, CDCl₃) δ 7.29-7.63 (m, 10H), 5.95 (brs, 1H), 4.73-4.93(m, 3H), 4.64 (m, 1H), 3.32 (t, 2H), 3.10 (d, 2H), 2.59 (t, 2H), 1.76(m, 2H), 1.54 (d, 6H), 1.28 (m, 3H), 0.90 (m, 1H); ESI MS m/z=456[C₂₇H₃₃N₇+H]⁺.

Example 221 Preparation of Compound 222

[1598] Prepared by the general methods described above: ¹H NMR (300 MHz,CDCl₃) δ 7.28-7.61 (m, 10H), 6.20 (brs, 1H), 4.70-4.91 (m, 3H),4.54-4.70 (m, 1H), 4.28 (brs, 1H), 3.75-3.90 (m, 1H), 3.08-3.11 (m, 1H),2.80-2.93 (m, 1H), 2.28-2.41 (d, 1H), 1.95-2.10 (m, 1H), 1.84-1.95 (m,1H), 1.70-1.84 (m, 1H), 1.60-1.70 (m, 1H), 1.52 (d, 6H), 1.22-1.41 (m,2H), 0.94-1.22 (m, 2H), 0.89 (t, 1H); ESI MS m/z=456 [C₂₇H₃₃N₇+H]⁺.

Example 222 Preparation of Compound 223

[1599] Prepared by the general Suzuki coupling conditions of 62 withboronic ester as shown in Scheme LXXV (58%): mp 200-206° C.; ¹H NMR (300MHz, (CD₃)₂SO) δ 7.22-8.00 (m, 9H), 6.10 (m, 2H), 4.40-4.76 (m, 4H),3.63 (m, 1H), 1.62-2.01 (m, 7H), 1.35-1.60 (d, 6H), 1.08-1.35 (m, 4H);ESI MS m/z=527 [C₃₀H₃₈N₈O+H]⁺.

Example 223 Preparation of Compound 224

[1600] Prepared by the general Suzuki coupling conditions of 61 and3,4-dimethylbenzeneboronic acid: ¹H NMR (300 MHz, CDCl₃) δ 7.53 (m, 3H),7.41 (d, 2H), 7.26-7.38 (m, 2H), 7.19 (d, 1H), 4.79 (s, 2H), 4.64 (m,1H), 3.80 (m, 1H), 3.12(m, 1H), 2.10-2.36 (m, 10H), 1.43-1.72(m, 8H),1.27(m, 4H);ESIMSm/z=484 [C₂₉H₃₇N₇+H]⁺.

Example 224 Preparation of 5-Bromo-2-cyanopyridine

[1601] 2,5-Dibromopyridine (20.0 g, 84.4 mmol) was dissolved indimethylformamide (422 mL). To the stirred solution was added copper(I)cyanide. After refluxing for 5 h, the mixture was cooled to roomtemperature and stored overnight. The reaction mixture was diluted withethyl acetate (1200 mL) and filtered through a Buchner funnel containingsand, Celite, and silica gel layers. The filtrate was concentrated to avolume of 400 mL. This organic liquid was diluted with water (300 mL)and the resulting liquid was extracted with ethyl acetate (2×200 mL).The organic extracts were combined, washed with water (2×300 mL) andbrine (1×250 mL), and dried over magnesium sulfate. After concentration,the product was purified via silica gel chromatography (50:50 ethylacetate/CH₂Cl₂) to afford the title compound (9.79 g).

Example 225 Preparation of Compound 225

[1602] Prepared by reation of 5-bromo-2-cyanopyridine withbenzeneboronic acid under standard Suzuki conditions (68%).

Example 226 Preparation of Compound 226

[1603] In a Parr shaker vessel were combined 225 (300 mg, 1.67 mmol),glacial acetic acid (25 mL), and 10% palladium on carbon catalyst (177mg, 0.167 mmol). The solution was agitated under 45 psig hydrogen gasfor 2 h. The resulting dispersion was filtered through a Buchner funnel.The filtrate was concentrated. Purification by acid/base extractionyielded 226 (240 mg, 78%).

Example 227 Preparation of Compound 229

[1604] Following the general schemes outlined above, compound 226 wastransformed into 227 (57% yield). Compound 227 was then transformed into228 in 83% yield. Compound 228 was then converted into compound 229 andthen its HCl salt (75%): ¹H NMR (300 MHz, CD₃OD) δ 9.11 (s, 1H), 8.90(d, 2H), 8.23 (d, 1H), δ 7.83 (m, 2H), 7.58 (m, 3H), 5.23 (m, 2H),4.70-5.01 (m, 1H), 3.72 (m, 1H), 3.09 (m, 1H), 1.80-2.15 (m, 4H),1.20-1.80 (m, 10H); ESI MS m/z=457 [C₂₆H₃₂N₈+H]⁺.

Example 228 Preparation of Compound 230

[1605] In a flask immersed in an ice water bath were combined 187 (30.0mg, 0.055 mmol), BOC-L-alanine (10.4 mg, 0.055 mmol), HATU (25.0 mg,0.066 mmol), N,N-diisopropylethylamine (0.050 mL, 0.274 mmol), anddimethylformamide (0.500 mL) for 10 min then warmed to room temperature.After stirring overnight, the reaction mixture was diluted withmethylene chloride (50 mL). The organic material was washed with 1 Mcitric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL),and brine (50 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. To remove remainingdimethylformamide, the resulting material was dissolved in ethyl acetate(50 mL) and rinsed with 5% lithium chloride solution (3×50 mL). Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo to yield 230 (28.0 mg, 79%): ¹H NMR (300 MHz,CDCl₃) δ 8.71 (s, 1H), 7.62-7.83 (m, 4H), 7.37-7.60 (m, 2H), 7.11 (m,1H), 6.11 (brs, 1H), 6.00 (d, 1H), 5.01 (brs, 1H), 4.81 (d, 2H), 4.64(m, 2H), 4.08 (m, 1H), 3.72 (m, 2H), 2.12 (m, 2H), 2.00 (m, 2H), 1.54(d, 6H), 1.43 (s, 9H), 1.15-1.38 (m, 7H); ESI MS m/z=646[C₃₄H₄₄FN₉O₃+H]⁺.

Example 229 Preparation of Compound 231

[1606] To a stirred solution of 230 in methylene chloride (2 mL) wasadded HCl in ethanol (2 mL). After stirring for 10 min, the solution wasconcentrated in vacuo to yield 231 (15.4 mg): ¹H NMR (300 MHz, CD₃OD) δ8.92 (s, 1H), 8.35-8.67 (m, 2H), 8.32 (d, 1H), 7.83 (t, 2H), 7.69 (m,1H), 7.40 (m, 1H), 4.65-5.20 (m, 3H), 3.60-4.00 (m, 2H), 1.80-2.30 (m,4H), 2.65 (d, 3H), 1.08-1.58 (m, 12H); ESI MS m/z=546 [C₂₉H₃₆FN₉O+H]⁺.

Example 230 Preparation of Compound 232

[1607] In a flask immersed in an ice water bath were combined 187 (30.0mg, 0.055 mmol), BOC-glycine (9.6 mg, 0.055 mmol), HATU (25.0 mg, 0.066mmol), NN-diisopropylethylamine (0.05 mL, 0.274 mmol), anddimethylformamide (0.50 mL) for 10 min then warmed to room temperature.After stirring overnight, the reaction mixture was diluted withmethylene chloride (50 mL). The organic material was washed with 1 Mcitric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL),and brine (50 mL). The organic layer was dried over magnesium sulfate,filtered, and concentrated in vacuo. To remove remainingdimethylformamide, the resulting material was dissolved in ethyl acetate(50 mL) and rinsed with 5% lithium chloride solution (3×50 mL). Theorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo to yield 232 (33.0 mg): ¹H NMR (300 MHz, CDCl₃) δ8.65 (s, 1H), 7.52-7.75 (m, 4H), 7.44 (s, 1H), 7.35 (q, 1H), 7.01 (t,1H), 6.05 (brs, 1H), 4.75 (d, 2H), 4.57 (m, 2H), 3.70 (m, 2H), 2.05 (m,2H), 1.92 (m, 2H), 1.46 (d, 6H), 1.40 (s, 9H), 1.20 (m, 6H); ESI MSm/z=632 [C₃₃H₄₂FN₉O₃+H]⁺.

Example 231 Preparation of Compound 233

[1608] To a stirred solution of 232 in methylene chloride (2 mL) wasadded HCl in ethanol (2 mL). After stirring for 10 min, the solution wasconcentrated in vacuo to yield 233 (10.6 mg): ¹H NMR (300 MHz, CD₃OD) δ8.95 (s, 1H), 8.28-8.75 (m, 3H), 7.79 (t, 2H), 7.69 (m, 1H), 7.46 (t,1H), 4.63-5.20 (m, 3H), 3.59-3.92 (m, 2H), 1.96-2.24 (m, 4H), 1.62 (d,6H), 1.05-1.52 (m, 8H); ESI MS m/z=532 [C₂₈H₃₄FN₉O+H]⁺.

Example 232 Preparation of Compound 239

[1609] Reaction of 234 with 1 under standard conditions provides 236(90%). Reaction of 236 with trans-1,4-cyclohexanediamine provides 237(95%). Boc protection of 237 followed by Suzuki coupling provides 238 in50% yield. Compound 238 was added to a 1:1 mixture of methylene chlorideand trifluroacetic acid. After stirring for 2 h, the solution wasconcentrated in vacuo. The resulting material was purified via silicagel chromatography (94:5:1 CH₂Cl₂:MeOH:NH₄OH) to afford 239:

[1610]¹H NMR (300 MHz, CDCl₃) δ 7.51-7.61 (m, 4H), 7.48 (s, 1H), 7.41(t, 2H), 7.31 (m, 3H), 5.61 (m, 1H), 4.63 (m, 2H), 3.87 (m, 2H), 3.18(m, 1H), 3.00 (t, 2H), 2.20-2.35 (m, 3H), 1.72 (m, 4H), 1.52 (d, 6H),1.25 (m, 4H).

Example 233 Preparation of Compound 240

[1611] Compound 239 was acetylated under the general conditionsdescribed above to provide 240 (73%). Salt formation occurred in 71%yield: ¹H NMR (300 MHz, CDCl₃) δ 7.28-7.62 (m, 10H), 5.67 (m, 1H), 4.64(m, 2H), 3.68-3.97 (m, 3H), 3.00 (t, 2H), 2.23 (m, 2H), 1.84-2.11 (m,7H), 1.53 (d, 6H), 1.30 (m, 4H).

Example 234 Preparation of Compound 241

[1612] Reductive amination of 239 with propionaldehyde followed by saltformation provided 241: ESI MS m/z=512 [C₃₁H₄₁N₇+H]⁺.

Example 235 Preparation of Compound 242

[1613] Compound 237 was Boc-protected and then treated with3-thiopheneboronic acid under standard Suzuki condition to prepare 242:¹H NMR (300 MHz, CDCl₃) δ 7.33-7.76 (m, 6H), 7.28 (m, 2H), 5.72 (brs,1H), 4.64 (m, 1H), 4.43 (m, 1H), 3.83 (m, 2H), 3.47 (m, 1H), 2.97 (t,2H), 2.21 (m, 2H), 2.08 (m, 2H), 1.53 (d, 6H), 1.46 (s, 9H), 1.29 (m,4H); ESI MS m/z=576 [C₃₁H₄₁N₇O₂S+H]⁺.

Example 236 Preparation of Compound 243

[1614] Compound 242 was deprotected with HCl in methanol to provide 243:

[1615]¹H NMR (500 MHz, CDCl₃) δ 7.68 (m, 1H), 7.54 (d, 2H), 7.47 (s,1H), 7.42 (s, 1 H), 7.37 (s, 1H), 7.28 (m, 2H), 5.68 (brs, 1H), 4.63 (m,2H), 3.85 (m, 3H), 2.99 (t, 2H), 2.71 (m, 1H), 2.18 (d, 2H), 1.90 (d,2H), 1.52 (d, 6H), 1.25 (m, 4H).

Example 237 Preparation of Compound 245

[1616] To a stirred solution of sodium hydride (423 mg, 17.6 mmol) intetrahydrofuran (12 mL), was added 4-phenylphenol (2.00 g, 11.8 mmol).After 1 h, BOC-2-aminoethylbromide (3.90 g, 17.6 mmol) was added to thesolution. After stirring overnight, the reaction mixture was quenchedwith 2 N potassium hydroxide solution (10 mL). The resulting mixture wasextracted with methylene chloride (12 mL). The organic layer wasconcentrated and the crude material was purified via silica gelchromatography to yield 245.

Example 238 Preparation of Compound 246

[1617] The protected amine 245 was added to 10 mL of an 1:1 mixture ofmethylene chloride and trifluoroacetic acid. After concentration, thematerial was diluted with 2 N potassium hydroxide solution (10 mL). Theaqueous layer was extracted with methylene chloride (2×10 mL). Theorganic extracts were combined, dried over magnesium sulfate, andconcentrated in vacuo to afford the product (400 mg). Reaction with 1under standard conditions provided 246 (91%).

Example 239 Preparation of Compound 248

[1618] Compound 246 was transformed into 247 under standard conditions(80%). Reaction of 247 with trans-1,4-cyclohexanediamine provided 248.Salt formation provided the target compound (68%): ¹H NMR (500 MHz,CDCl₃) δ 7.53 (m, 4H), 7.40 (m, 2H), 7.29 (m, 2H), 7.00 (d, 2H), 5.93(brs, 1H), 4.61 (m, 2H), 4.22 (t, 2H), 4.02 (m, 2H), 3.78 (m, 1H), 2.70(m, 1H), 2.18 (d, 2H), 1.90 (d, 2H), 1.53 (d, 6H), 1.25 (m, 4H).

Example 240 Preparation of Compound 250

[1619] Reductive amination of 248 with propionaldehyde and saltformation under standard conditions described above provided 250: ESI MSm/z=528 [C₃₁H₄₁N₇O+H]⁺.

Example 241 Preparation of Compound 249

[1620] N-Acetylation of 248 and salt formation under standard conditionsprovided 249: ¹H NMR (300 MHz, CDCl₃) δ 6.95-7.60 (m, 10H), 5.97 (brs,1H), 5.24 (d, 1H), 4.63 (m, 2H), 4.23 (t, 2H), 4.02 (m, 2H), 3.78 (m,2H), 2.21 (m, 2H), 2.04 (m, 2H), 1.94 (s, 3H), 1.55 (d, 6H), 1.30 (m,4H).

Example 242 Preparation of Compound 255

[1621] Utilizing reaction conditions described in general above, 251 wasconverted to 252 (100%). Compound 252 was converted to 253 then 254 andthen Boc-protected to make 255 (21%).

Example 243 Preparation of Compound 256

[1622] Compound 255 was treated with phenylboronic acid under standardSuzuki condions. The product was dissolved in methanol and immersed inan ice water bath. Hydrogen chloride gas was bubbled through thesolution. The solution was concentrated in vacuo and the resultingmaterial was purified via preparatory HPLC(acetonitrile/water/trifluoroacetic acid) to yield 256 (8 mg).

Example 244 Preparation of Compound 257

[1623] Compound 255 was treated with 3-thiopheneboronic acid understandard Suzuki conditions. The product was dissolved in methanol andimmersed in an ice water bath. Hydrogen chloride gas was bubbled throughthe solution. The solution was concentrated in vacuo and the resultingmaterial was purified via preparatory HPLC(acetonitrile/water/trifluoroacetic acid) to yield 257: ¹H NMR (300 MHz,CDCl₃) δ 7.31-7.58 (m, 8H), 5.99 (brs, 1H), 5.10-5.50 (m, 1H), 4.49-4.69(m, 2H), 3.67 (m 1H), 2.67 (m, 1H), 2.13 (m, 2H), 1.90 (m, 2H), 1.62 (d,3H), 1.53 (d, 6H), 1.21 (m, 4H).

Example 245 Preparation of Compound 258

[1624] Reaction of 75 with propionoyl chloride under standard conditionsprovides 258 (89%): mp 182-183° C.

Example 246 Preparation of Compound 259

[1625] Reaction of 75 with methyl chloroformate under standardconditions provides 259 (68%): mp 148-150° C.

Example 247 Preparation of Compound 260

[1626] Reaction of 75 with methanesulfonyl chloride under standardconditions provides 260 (56%): mp 143-145° C.

Example 248 Preparation of Compound 261

[1627] Reaction of 75 with cyclopropanecarbonyl chloride under standardconditions provides 261 (87%): mp 196-204° C.

Example 249 Preparation of Compound 262

[1628] Compound 75 (250 mg, 0.549 mmol) and succinic anhydride (60.0 mg,0.600 mmol) were dissolved in xylene (30 mL). A few drops ofdimethylformamide were added to the solution. After refluxing for 48 h,the mixture was concentrated in vacuo. The resulting material waspurified via silica gel chromatography (99.5:0.5 CH₂Cl₂/MeOH) andrecrystallized from CH₂Cl₂ in hexanes (1:10) to yield 262 (30.0 mg,10%): mp 141-147° C.

Example 250 Preparation of Compound 263

[1629] The amine 75 (200 mg, 0.439 mmol) was dissolved in methylenechloride (15 mL). The stirred solution was cooled to −78° C. andN,N-diisopropylethylamine (113 mg, 0.878 mmol) andtrifluromethylsulfonylchloride (81.4 mg, 0.483 mmol) were added. After30 min, the solution was warmed to room temperature. The mixture wascooled to −78° C. and another 1.10 equivalents oftrifluoromethylsulfonylchloride and 1.50 equivalents ofN,N-diisopropylethylamine were added. After warming to room temperature,the solution was concentrated. The resulting material was purified viasilica gel chromatography (99:1 CH₂Cl₂/MeOH) and recrystallization fromether in hexanes to afford 263 (60 mg, 23%): mp 131-136° C.

Example 251 Preparation of Compound 264

[1630] Prepared by standard Suzuki coupling of 61 to provide 264 (65%):mp 186-190 C.

Example 252 Preparation of Compound 265

[1631] N-Acetylation of 264 under standard conditions provides 265(37%): mp 241-246° C.

Example 253 Preparation of Compound 266

[1632] Suzuki coupling of 61 with 2-chlorobenzeneboronic acid provides266 (13%): API MS m/z 490 [C₂₇H₃₂ClN₇+H]⁺.

Example 254 Description of Biological Assays

[1633] A. Immunopurification of CyclinA/cdk2 and CyclinE/cdk2 Complexes.

[1634] CyclinA/cdk2 and cyclinE/cdk2 assays were carried out withcyclin/cdk complexes isolated from HeLa S-3 suspension cultures. HeLacells were grown in spinner flasks at 37° C. in Joklik's modifiedminimum essential media (MEM) supplemented with 7% horse serum. Aftergrowing in medium supplemented with 2 mM thymidine for 16-18 h, cultureswere arrested at the G1/S border and cyclinA/cdk2 and cyclinE/cdk2 wereisolated from cell lysates by immunoprecipitation with antibodiesspecifically directed against each cyclin subunit. Rabbit anti-cyclinA(H-432) and the mouse monoclonal antibody against cycline (HE111) werepurchased from Santa Cruz Biotechnology. Cells blocked at theappropriate stage of the cell cycle were disrupted in lysis buffer (50mM Tris, pH 8.0, 250 mM NaCl, 0.5% NP-40 plus protease and phosphataseinhibitors) and centrifuged at 10,000×g to remove insoluble material. Toisolate cyclin/cdk complexes, 1 μg of anti-cyclin antibody was incubatedwith lysate from 1×10⁷ cells for 1 h at 4° C. Protein A-coated agarosebeads were then added for 1 h to collect antibody-bound immunecomplexes. The immobilized cyclin/cdk complexes were then washed 4×withlysis buffer to reduce nonspecific protein binding. The complexes werethen washed 1×in kinase assay buffer (50 mM Tris-HCl, pH 7.4, 10 mMMgCl₂, 1 mM DTT) and aliquoted into individual assay tubes.

[1635] B. Immunopurification of CyclinB/cdkl Complex.

[1636] HeLa cells are blocked at the G1/S border by culturing in thepresence of 2 mM thymidine for 20 h. The cells are then rinsed 3×inphosphate buffered saline and resuspended in regular medium. After 4 hof culture, the mitotic blocker, nocodazole is added to a finalconcentration of 75 ng/ml. Sixteen hours later, the cells are harvestedby centrifugation, washed in PBS, and lysed in cold Lysis Buffer (50 mMTris pH 8.0, 250 mM NaCl, 0.5% NP-40, 1 mM DTT, 25 μg/ml leupeptin, 25μg/ml aprotinin, 15 μg/ml benzamidine, 1 mM PMSF, 50 mM sodium fluoride,1 mM sodium orthovanadate) for 15 min at 1×10⁷ cells/ml. The lysate isthen clarified by centrifugation at 10,000×g for 10 min. The supernatantis collected and diluted 1:5 with Lysis Buffer. Monoclonal antibodyagainst cyclinB (GNS1) is added to the supernatant to a finalconcentration of 5 μg/ml and shaken at 4° C. for 2 h. The immunecomplexes are then collected by the addition of 200 μl of proteinagarose beads for 1 h. The beads are washed 4×in lysis buffer and 1×inkinase assay buffer.

[1637] C. Protein Kinase Assays and Determination of IC₅₀ Values.

[1638] CyclinA/cdk2 assays were carried out with complexes isolated from0.5×10⁶ cells. CyclinE/cdk2 assays were carried out with complexesisolated from 4×10⁶ cells. CyclinB/cdkl assays were carried out withcomplexes isolated from 4×10⁴ cells. After centrifugation, the washbuffer was removed and the complexes resuspended in 15 μl of kinaseassay buffer (kinase wash buffer+167 μg/ml histone H1). Compounds beingtested for inhibition were added prior to the addition of [γ ³²P] ATP toa final concentration of 15 μM. The tubes were incubated at 30° C. for 5min and the reactions were stopped by the addition of an equal volume of2×SDS-PAGE sample buffer. The samples were then subjected toelectrophoresis on 10% SDS-PAGE to resolve the histone H1 from otherreaction components. The amount of radioactive phosphate transferred tohistone H1 was quantified on a Storm Phosphorimager (MolecularDynamics).

[1639] Prior to the protein kinase assay, test compounds were dissolvedin DMSO at a concentration of 25 mM and were diluted to produce finalconcentrations of 0.1, 1.0, and 10.0 μM in the kinase assays. Toeliminate possible effects of differences in DMSO concentration, theDMSO was kept constant at 0.04%, including the control reaction.Duplicate assays were performed at each concentration. The activity wasplotted as the percent of activity in the absence of added test compoundversus test compound concentration. IC₅₀ values were calculated usingGraphPad Prism data analysis software.

[1640] D. Measuring the Inhibition of Cell Growth.

[1641] Growth inhibition (GI₅₀) values were measured with HeLa S-3 cellsselected for growth on plastic. The procedure was based on the protocolof Skehan et al. (Skehan, P., et al., J. Natl. Cancer Inst.,82:1107-1112 (1990), which is hereby incorporated by reference) HeLacells were plated at 2×1 cells/well in 96 well plates. One day later, acontrol plate was fixed by addition of TCA to 5%. After five rinses withtap water the plate was air dried and stored at 4° C. Test compoundswere added to the remaining plates at 10-fold dilutions between 0.01 and100 μM. Two days later all plates were fixed as described above. Cellswere then stained by the addition of 100 μl per well of 0.4%sulforhodamine B (SRB) in 1% acetic acid for 30 min at 4° C. Wells werethen quickly rinsed 5×with acetic acid (1%) and allowed to air dry. TheSRB was then solubilized by the addition of 100 μl per well ofunbuffered 10 mM Tris base. Dye was quantified by measuring absorbanceat 490 nm on a Molecular Devices kinetic microplate reader. Growth ateach inhibitor concentration relative to the untreated control wascalculated according to the following equation: percentgrowth=100×(T−T_(o))/(C−T_(o)), where T was the average optical density(OD) of the test wells after 2 days of treatment, T_(o) was the averageOD of the wells in the control plate on day 0 and C was the average ODof untreated wells. Plots of percent growth versus inhibitorconcentration were used to determine the GI₅₀.

[1642] The data below shown in Table 2 summarizes the in vitrocyclin/cdk inhibition constants (IC₅₀) and growth inhibition constants(GI₅₀) of HeLa Cells for the compounds of the current invention.Replicate experimental results are summarized below. TABLE 2 In VitroCyclin/cdk Inhibition (IC₅₀) and Growth Inhibition (GI₅₀) of HeLa CellsFor Compounds of the Current Invention. Com- IC₅₀ CyclinA/ IC₅₀ CyclinE/IC₅₀ CyclinB/ GI₅₀ HeLa pound cdk2 (μM) cdk2 (μM) cdk1 (μM) Cells (μM)5 >10 12 7 5 0.4 0.6 >10 12 2 1 3 0.06 0.7 3 0.003 0.9 0.5 0.001 0.2 0.10.02 0.000 1 13 4 2 4 3 1 0.3 2 0.8 0.9 14 3 0.4 7 0.4 3 2 0.03 0.03 171 1 10 0.4 2 0.9 3 0.6 1 0.2 11 0.25 >10 9 0.4 10 2 0.3 0.4 25 1 4 >10 26 1 >10 0.4 >10 9 >1 32 2 3 — 5 5 0.9 0.7 33 >10 4 >10 1 13 6 2 8 0.9 3412 5 >10 7 13 2 6 7 36 >10 >10 >10 20 >10 >10 20 >10 >10 38 >10 >10 >100.6 >10 >10 1 0.6 40 >10 >10 >10 9 >10 >10 25 >10 43 >10 >10 >104 >10 >10 4 8 46 >10 6 >10 25 8 3 >10 48 22 1 >10 0.3 6 5 0.6 0.550 >10 >10 >10 3 7 9 >10 53 >10 15 >10 0.2 >10 4 0.3 0.5 58 11 2 12 2 44 0.5 0.7 60 >10 12 >10 7 0.4 >10 6 73 >50 4 >10 0.3 14 12 0.5 >10 >100.3 >10 >10 0.5 74 5 2 6 0.2 2 3 0.01 1 2 0.05 0.03 0.05 75 3 3 6 0.090.02 0.005 76 12 3 6 0.07 11 5 0.01 3 2 0.06 0.2 0.04 77 >10 4 >100.15 >10 14 0.5 0.3 78 0.9 0.6 0.8 0.05 0.9 0.3 0.8 0.025 0.7 0.2 0.080.002 79 10 2 3 0.07 0.5 0.1 0.007 1 0.08 0.004 0.480 >10 >10 >10 >100 >10 4 >10 2 86 0.9 0.4 2 0.2 0.7 0.2 0.03 0.4 0.40.01 0.6 0.03 0.01 0.2 87 4 1 5 0.07 2 0.3 0.01 0.5 0.1 0.004 0.006 0.030.006 0.001 0.0001 88 3 4 >10 0.1 >10 >10 0.05 2 5 0.04 0.005 93 0.20.09 0.9 0.3 0.3 0.1 0.08 0.3 94 0.6 0.3 0.4 0.1 0.2 0.3 0.07 0.4 95 1 14 0.08 2 0.7 0.003 0.0005 96 8 4 6 0.04 0.01 97 >10 3 10 3 98 62 >10 >10 2 2 11 99 >10 9 >10 5 100 >10 4 >10 0.6 101 3 1 4 1 0.9 0.7 1102 >10 4 — 4 103 0.6 0.2 1 0.03 0.7 0.2 0.008 0.02 0.01 104 7 1 2 0.4 81 0.2 106 11 3 — 0.3 4 1 0.1 107 1 2 — 0.4 4 0.3 108 10 >10 — 3 >10 >105 109 0.6 0.1 — 0.04 <0.0001 110 0.6 2 — 0.02 0.03 0.02 0.01 11 0.2 0.07— 0.02 0.0006 112 2 2 — <0.001 0.002 0.02 0.006 0.0006 113 0.4 0.3 —<0.001 0.00001 0.03 0.001 0.02 114 3 0.7 — >10 115 3 0.4 — 3 116 >10 >10— >10 >10 117 >10 3 — 3 118 6 1 — >10 >10 123 0.2 0.04 — <0.001 <0.0010.0001 124 2 0.8 — 0.003 <0.001 <0.0001 130 — — — >10 >10 131 — — — 3 2132 — — — 4 3 133 — — — >10 >10 134 — — — 2 3 135 — — — 4 3 137 — — —0.05 0.06 0.05 139 — — — 0.2 0.07 140 — — — 1 2 142 — — — 0.4 0.5 144 —— — 0.4 0.4 146 — — — 0.7 0.3 148 — — — 1 1 149 — — — 0.3 0.2 150 — — —0.3 0.2 151 — — — 0.8 0.6 152 — — — 0.7 0.3 153 — — — 3 2 154 — — — 0.60.9 155 — — — 0.5 0.8 156 — — — 3 2 157 — — — 0.4 0.5 158 — — — 0.6 0.4159 — — — 4 3 160 — — — 0.2 0.3 161 — — — 0.2 0.4 162 — — — 0.2 0.3 163— — — 2 3 164 — — — 0.2 0.1 165 — — — 0.2 0.1 166 — — — 4 2 167 — — — 20.9 168 — — — 4 3 169 — — — 0.5 0.3 170 — — — 4 2 171 — — — 3 3 172 — —— 0.3 0.3 173 — — — 3 3 174 — — — 0.04 0.03 0.1 0.06 0.4 0.4 175 — — —0.6 0.3 177 — — — 0.2 0.06 0.06 178 — — — 0.4 0.2 179 — — — 0.1 0.050.05 180 — — — 0.4 0.3 181 — — — 0.04 182 — — — 0.3 0.3 187 — — — 0.050.03 188 — — — 0.2 0.07 194 — — — 0.06 0.04 199 — — — 0.2 0.09 200 — — —0.3 0.2 206 — — — 0.2 0.2 207 — — — 0.4 0.2 208 — — — 4 3 209 — — — 2 2210 — — — 3 4 211 — — — 0.6 0.3 212 — — — 5 3 213 — — — 3 2 214 — — — 55 215 — — — 2 3 216 — — — 0.5 0.5 217 — — — 4 4 218 — — — 3 5 219 — — —0.4 0.6 221 — — — 2 2 222 — — — 1 2 223 — — — 0.04 0.1 224 — — — 2 2 229— — — 0.4 230 — — — 0.3 231 — — — 0.04 232 — — — 0.3 233 — — — 0.5 239 —— — 4 6 240 — — — 8 8 241 — — — 7 4 242 — — — 7 >10 243 — — — 3 3 248 —— — 3 4 249 — — — >10 >10 250 — — — 3 6 256 — — — 4 3 257 — — — 3 3 258— — — 0.2 0.3 0.4 259 — — — 0.3 0.4 0.7 260 — — — 0.2 0.1 0.2 261 — — —0.3 0.3 0.3 262 — — — 0.3 0.2 0.5 263 — — — 2 3 4 264 — — — 0.3 0.3 0.5265 — — — 0.3 0.3 0.4 266 — — — 0.3 0.3 0.5 267 — — — 0.8 0.6

[1643] The data below shown in Table 3 summarizes the in vitrocyclin/cdk inhibition (IC₅₀) and growth inhibition (GI₅₀) of HeLa Cellsfor several reference compounds in comparison to several compounds ofthe current invention. The chemical structures are provided. TABLE 3 InVitro cyclin/cdk Inhibition (IC₅₀) and Growth Inhibition (GI₅₀) of HeLaCells For Reference Compounds in Comparison to Several Compounds of theCurrent Invention. IC₅₀ IC₅₀ IC₅₀ GI₅₀ HeLa CyclinA/cdk2 CyclinE/cdk2CyclinB/cdk1 Cells Compound Structure (μM) (μM) (μM) (μM) Olomoucine

0.5-24 (n>10) 1-14 (n>10) 7-23 (n>10) 75 Roscovitine

2.1 4 3 0.04 0.7 — 30 25 30 >10 25 Flavopiridol

0.06 0.2 0.6 0.04 0.06 (n = 2) 0.18 125

1 0.1 0.6 3 126

0.6 0.8 0.06 0.06 2 0.2 2 4 6  74

5 2 6 0.2 0.01 0.05 127

0.3-2 (n>15) 0.04-0.07 (n>15) 0.5-2 (n>15) 7-15 (n>5)  88

3 4 >10 0.1 0.05 0.04

[1644] The following data in Tables 4, 5, 6, and 7 summarize the growthinhibition properties of several compounds of the current invention andolomoucine against 60-human transformed cell lines. These data werecooperatively obtained at the National Cancer Institute in their 60-cellline growth inhibition assay according to published procedures (Boyd, M.R., “Anticancer Drug Development Guide,” Preclinical Screening, ClinicalTrials, and Approval; Teicher B. Ed.; Humana Press; Totowa, N.J., 23-42(1997), which is hereby incorporated by reference). TABLE 4 In VitroGrowth Inhibition (GI₅₀) of NCI Human Transformed Cell Lines of SeveralCompounds of the Current Invention. 73 GI₅₀ 17 GI₅₀ 33 GI₅₀ 38 GI₅₀Cancer Type Cell Line (μM) (μM) (μM) (μM) Breast BT-549 0.25 0.40 51.30.32 Breast HS 578T 0.10 6.31 — — Breast MCF7 0.16 0.16 5.2 0.20 BreastMDA-MB-231/ 0.50 — — 0.06 ATCC Breast MDA-MB-435 0.25 0.20 4.9 0.05Breast MDA-N 0.13 0.11 — — Breast NCI/ADR-RES 0.40 0.28 6.3 0.32 BreastT-47D 0.25 0.13 3.9 0.25 CNS SF-268 0.16 0.04 6.3 0.20 CNS SF-295 0.250.19 7.8 0.50 CNS SF-539 0.76 0.40 89.1 1.26 CNS SNB-19 0.43 0.14 38.00.50 CNS SNB-75 0.02 0.02 — — CNS U251 0.32 0.40 3.7 0.20 Colon COLO 2050.28 0.05 7.8 0.16 Colon HCC-2998 0.20 0.03 >1000 7.94 Colon HCT-1160.20 0.16 6.2 0.32 Colon HCT-15 0.18 0.04 8.9 0.25 Colon HT29 — 0.10 8.90.25 Colon KM12 0.13 0.03 4.1 0.16 Colon SW-620 — 0.01 2.9 0.03 LeukemiaCCRF-CEM 0.25 0.16 4.6 0.20 Leukemia HL-60(TB) — — 3.2 0.04 LeukemiaK-562 0.16 0.16 3.1 0.25 Leukemia MOLT-4 0.32 0.25 3.8 0.25 LeukemiaRPMI-8226 0.03 0.03 1.5 — Leukemia SR — 0.50 4.5 3.98 Melanoma LOX IMVI— 0.32 16.6 0.40 Melanoma M14 0.03 0.03 7.8 0.05 Melanoma MALME-3M 0.2719.95  11.7 0.25 Melanoma SK-MEL-2 0.63 1.00 >1000 2.00 MelanomaSK-MEL-28 0.45 0.12 5.9 0.03 Melanoma SK-MEL-5 0.25 0.32 16.2 0.32Melanoma UACC-257 0.16 0.20 75.9 0.50 Melanoma UACC-62 0.30 0.27 8.31.00 Non-Small Cell A549/ATCC 0.03 0.03 4.6 0.13 Lung Non-Small CellEKVX 0.25 2.51 6.9 0.20 Lung Non-Small Cell HOP-62 0.06 0.20 >1000 0.32Lung Non-Small Cell HOP-92 1.00 1.58 — 0.32 Lung Non-Small Cell NCI-H2260.22 0.11 — — Lung Non-Small Cell NCI-H23 0.32 0.16 26.3 0.32 LungNon-Small Cell NCI-H322M 0.16 >1000 38.9 0.40 Lung Non-Small CellNCI-H460 0.40 0.41 25.7 3.16 Lung Non-Small Cell NCI-H522 — — 4.2 — LungOvarian IGROV1 0.32 0.20 10.0 0.16 Ovarian OVCAR-3 0.30 0.65 >1000 1.00Ovarian OVCAR-4 0.32 0.32 31.6 1.26 Ovarian OVCAR-5 0.25 0.26 >1000 0.40Ovarian OVCAR-8 — 0.13 6.6 0.25 Ovarian SK-OV-3 0.95 0.40 >1000 3.98Prostate DU-145 7.08 0.63 17.8 1.26 Prostate PC-3 0.35 0.20 >1000 0.40Renal 786-0 0.20 0.25 18.6 0.32 Renal A498 2.88 1.58 — 1.26 Renal ACHN0.32 0.40 5.2 2.00 Renal CAKI-1 1.66 0.13 4.4 0.20 Renal RXF 393 0.090.02 13.2 0.13 Renal SN12C — 0.56 — — Renal TK-10 — — 8.3 0.40 RenalUO-31 0.06 0.10 8.1 0.13

[1645] TABLE 5 In Vitro Growth Inhibition (GI₅₀) of NCI HumanTransformed Cell Lines of Several Compounds of the Current Invention.Cancer 43 GI₅₀ 48 GI₅₀ 75 GI₅₀ 76 GI₅₀ Type Cell Line (μM) (μM) (μM)(μM) Breast BT-549 4.0 0.01 <0.01 <0.01 Breast HS 578T — 0.03 <0.01<0.01 Breast MCF7 2.7 0.25 <0.01 <0.01 Breast MDA-MB-231/ 3.2 0.09 <0.01<0.01 ATCC Breast MDA-MB-435 2.1 — — — Breast MDA-N — 0.02 <0.01 <0.01Breast NCI/ADR-RES 5.2 0.12 0.48 0.015 Breast T-47D 2.2 0.15 <0.01 <0.01CNS SF-268 3.0 <0.01 <0.01 <0.01 CNS SF-295 4.0 0.24 <0.01 <0.01 CNSSF-539 3.4 0.38 0.02 0.054 CNS SNB-19 5.0 0.02 <0.01 <0.01 CNS SNB-75 —<0.01 <0.01 <0.01 CNS U251 2.3 0.17 <0.01 0.020 Colon COLO205 1.6 0.03<0.01 <0.01 Colon HCC-2998 3.4 — — — Colon HCT-116 2.1 0.19 <0.01 0.014Colon HCT-15 3.9 0.02 0.03 <0.01 Colon HT29 3.6 <0.01 <0.01 <0.01 ColonKMl2 2.3 0.02 <0.01 <0.01 Colon SW-620 1.6 <0.01 <0.01 <0.01 LeukemiaCCRF-CEM 2.8 0.03 <0.01 <0.01 Leukemia HL-60(TB) 2.1 — — — LeukemiaK-562 3.1 0.16 <0.01 <0.01 Leukemia MOLT-4 2.0 0.05 <0.01 <0.01 LeukemiaRPMI-8226 — <0.01 <0.01 <0.01 Leukemia SR 2.2 0.16 <0.01 <0.01 MelanomaLOX IMVI 3.4 0.19 <0.01 <0.01 Melanoma M14 2.2 <0.01 <0.01 <0.01Melanoma MALME-3M 3.0 0.13 <0.01 <0.01 Melanoma SK-MEL-2 61.7 0.48 0.020.112 Melanoma SK-MEL-28 2.3 <0.01 <0.01 <0.01 Melanoma SK-MEL-5 2.10.17 0.01 0.013 Melanoma UACC-257 4.8 0.04 <0.01 <0.01 Melanoma UACC-623.3 0.10 0.01 0.018 Non-Small Cell A549/ATCC 4.1 <0.01 <0.01 <0.01 LungNon-Small Cell EKVX 2.8 — — — Lung Non-Small Cell HOP-62 3.3 0.03 <0.01<0.01 Lung Non-Small Cell HOP-92 2.6 0.46 <0.01 0.017 Lung Non-SmallCell NCI-H226 — — — — Lung Non-Small Cell NCI-H23 4.3 0.07 <0.01 <0.01Lung Non-Small Cell NCI-H322M 3.5 0.03 <0.01 <0.01 Lung Non-Small CellNCI-H460 3.2 0.25 <0.01 0.047 Lung Non-Small Cell NCI-H522 — <0.01 <0.01<0.01 Lung Ovarian IGROV1 3.4 0.23 <0.01 <0.01 Ovarian OVCAR-3 9.3 0.17<0.01 <0.01 Ovarian OVCAR-4 8.9 0.20 <0.01 <0.01 Ovarian OVCAR-5 3.60.16 <0.01 <0.01 Ovarian OVCAR-8 3.9 0.10 <0.01 <0.01 Ovarian SK-OV-372.4 1.38 0.03 0.051 Prostate DU-145 2.6 0.55 <0.01 0.043 Prostate PC-338.9 0.23 <0.01 <0.01 Renal 786-0 3.1 0.25 <0.01 <0.01 Renal A498 3.00.39 0.01 <0.01 Renal ACHN 3.1 0.25 0.02 0.025 Renal CAKI-1 3.0 — — —Renal RXF 393 1.9 <0.01 <0.01 <0.01 Renal SN12C — 0.03 <0.01 <0.01 RenalTK-10 3.2 0.37 <0.01 0.013 Renal UO-31 2.8 <0.01 0.03 <0.01

[1646] TABLE 6 In Vitro Growth Inhibition (GI₅₀) of NCI HumanTransformed Cell Lines of Several Compounds of the Current Invention. 79GI₅₀ 87 GI₅₀ 12 GI₅₀ Cancer Type Cell Line (μM) (μM) (μM) Breast BT-549<0.01 0.02 0.041 Breast HS 578T <0.01 <0.01 <0.005 Breast MCF7 <0.010.04 <0.005 Breast MDA-MB-231/ <0.01 <0.01 <0.005 ATCC Breast MDA-MB-435<0.01 <0.01 <0.005 Breast MDA-N <0.01 0.0 14 <0.005 Breast NCI/ADR-RES0.86 0.28 1.26 Breast T-47D <0.01 0.048 0.0088 CNS SF-268 <0.01 <0.01<0.005 CNS SF-295 <0.01 0.047 0.018 CNS SF-539 <0.01 0.081 0.022 CNSSNB-19 <0.01 0.038 0.016 CNS SNB-75 <0.01 0.012 <0.005 CNS U251 <0.010.028 0.0078 Colon COLO 205 <0.01 <0.01 <0.005 Colon HCC-2998 <0.01<0.01 <0.005 Colon HCT-116 <0.01 0.037 0.0089 Colon HCT-15 <0.01 0.0660.17 Colon HT29 <0.01 <0.01 <0.005 Colon KM12 <0.01 <0.01 <0.005 ColonSW-620 <0.01 <0.01 <0.005 Leukemia CCRF-CEM <0.01 <0.01 <0.005 LeukemiaHL-60(TB) <0.01 <0.01 <0.005 Leukemia K-562 <0.01 0.024 <0.005 LeukemiaMOLT-4 <0.01 0.02 <0.005 Leukemia RPMI-8226 <0.01 <0.01 <0.005 LeukemiaSR <0.01 0.032 <0.005 Melanoma LOX IMVI <0.01 0.027 <0.005 Melanoma M14<0.01 <0.01 <0.005 Melanoma MALME-3M <0.01 0.024 0.0 10 MelanomaSK-MEL-2 <0.01 0.056 0.0096 Melanoma SK-MEL-28 <0.01 <0.01 0.01 MelanomaSK-MEL-5 <0.01 0.028 0.0 14 Melanoma UACC-257 <0.01 0.0 17 0.008Melanoma UACC-62 <0.01 0.045 0.027 Non-Small Cell Lung A549/ATCC <0.01<0.01 <0.005 Non-Small Cell Lung EKVX <0.01 0.08 1 0.023 Non-Small CellLung HOP-62 <0.01 0.01 <0.005 Non-Small Cell Lung HOP-92 <0.01 0.0880.011 Non-Small Cell Lung NCI-H226 <0.01 0.0.052 0.021 Non-Small CellLung NCI-H23 <0.01 0.022 <0.005 Non-Small Cell Lung NCI-H322M <0.01 0.021 <0.005 Non-Small Cell Lung NCI-H460 <0.01 0.22 0.0 15 Non-Small CellLung NCI-H522 <0.01 <0.01 <0.005 Ovarian IGROV1 <0.01 0.052 0.013Ovarian OVCAR-3 <0.01 0.05 0.012 Ovarian OVCAR-4 <0.01 0.048 <0.005Ovarian OVCAR-5 <0.01 0.051 0.017 Ovarian OVCAR-8 <0.01 0.03 3 0.0076Ovarian SK-OV-3 <0.01 0.35 0.0 18 Prostate DU-145 <0.01 0.22 0.017Prostate PC-3 <0.01 0.018 <0.005 Renal 786-0 <0.01 0.047 0.0065 RenalA498 <0.01 0.10 0.016 Renal ACHN <0.01 0.19 0.039 Renal CAKI-1 <0.010.064 0.03 8 Renal RXF393 <0.01 0.011 <0.005 Renal SN12C <0.01 <0.01<0.005 Renal TK-10 <0.01 0.029 0.01 Renal UO-31 <0.01 0.016 0.063

[1647] TABLE 7 In Vitro Growth Inhibition (GI₅₀) of NCI HumanTransformed Cell Lines of Several Compounds of the Current Invention andOlomoucine. Olo- mou- cine 74 GI₅₀ 78 GI₅₀ 77 GI₅₀ GI₅₀ Cancer Type CellLine (μM) (μM) (μM) (μM) Breast BT-549 0.16 0.04 <0.01 79 Breast HS 578T<0.01 — <0.01 63 Breast MCF7 <0.01 <0.01 0.03 50 Breast MDA-MB-231/<0.01 <0.01 0.04 100 ATCC Breast MDA-MB-435 — — — 63 Breast MDA-N <0.01<0.01 0.01 79 Breast NCIADR-RES 0.24 14.45 0.03 100 Breast T-47D <0.010.03 0.01 63 CNS SF-268 <0.01 — <0.01 50 CNS SF-295 <0.01 0.21 0.04 79CNS SF-539 0.07 — 0.22 32 CNS SNB-19 <0.01 <0.01 0.03 63 CNS SNB-75<0.01 <0.01 <0.01 25 CNS U251 <0.01 0.02 0.09 50 Colon COLO 205 <0.01<0.01 0.02 32 Colon HCC-2998 — <0.01 — 63 Colon HCT-116 <0.01 0.03 0.0540 Colon HCT-15 <0.01 1.48 <0.01 40 Colon HT29 <0.01 <0.01 <0.01 63Colon KM12 <0.01 <0.01 <0.01 40 Colon SW-620 <0.01 <0.01 <0.01 40Leukemia CCRF-CEM <0.01 — <0.01 40 Leukemia HL-60(TB) — <0.01 — 40Leukemia K-562 <0.01 0.02 0.02 100 Leukemia MOLT-4 <0.01 <0.01 0.01 63Leukemia RPMI-8226 <0.01 <0.01 <0.01 50 Leukemia SR <0.01 — 0.02 25Melanoma LOX IMVI <0.01 — 0.04 32 Melanoma M14 <0.01 <0.01 <0.01 100Melanoma MALME-3M 0.01 0.01 0.05 100 Melanoma SK-MEL-2 0.06 0.02 0.51100 Melanoma SK-MEL-28 <0.01 0.01 <0.01 50 Melanoma SK-MEL-5 0.06 0.100.08 40 Melanoma UACC-257 <0.01 0.02 0.02 79 Melanoma UACC-62 0.04 0.030.12 32 Non-Small Cell A549/ATCC <0.01 <0.01 <0.01 50 Lung Non-SmallCell EKVX — 0.05 — 100 Lung Non-Small Cell HOP-62 <0.01 0.02 <0.01 32Lung Non-Small Cell HOP-92 0.03 — 0.13 50 Lung Non-Small Cell NCI-H226 —0.02 — 50 Lung Non-Small Cell NCI-H23 <0.01 0.01 0.01 79 Lung Non-SmallCell NCI-H322M <0.01 <0.01 <0.01 63 Lung Non-Small Cell NCI-H460 <0.010.05 0.22 63 Lung Non-Small Cell NCI-H522 <0.01 <0.01 <0.01 40 LungOvarian IGROV1 <0.01 <0.01 0.09 40 Ovarian OVCAR-3 <0.01 0.03 0.02 79Ovarian OVCAR-4 <0.01 0.02 <0.01 100 Ovarian OVCAR-5 0.03 <0.01 0.04 40Ovarian OVCAR-8 <0.01 0.02 0.02 63 Ovarian SK-OV-3 0.22 0.06 0.19 100Prostate DU-145 0.02 0.06 0.13 40 Prostate PC-3 <0.01 <0.01 0.02 100Renal 786-0 <0.01 0.04 0.03 63 Renal A498 0.03 0.03 0.03 32 Renal ACHN0.03 0.32 0.11 25 Renal CAKI-1 — 0.79 — 32 Renal RXF 393 <0.01 <0.01<0.01 20 Renal SN12C <0.01 <0.01 <0.01 100 Renal TK-10 <0.01 0.07 0.0563 Renal UO-31 0.01 0.17 <0.01 32

[1648] The following data in Table 8 summarize the in vivo properties ofseveral compounds of the current invention. These data werecooperatively obtained at the National Cancer Institute in their HollowFiber Assay according to published procedures (Hollingshead, M. G., etal “In Vivo Cultivation of Tumor Cells in Hollow Fibers,” Life Sciences,1995, 57(2), 131-141 which is hereby incorporated by reference). TABLE 8In Vivo Evaluation of Several Compounds of the Current Invention. MTD IPSC Compound (mg/kg) Score score Cell Kill Cell Types Killed 73 100 2 0 N— 17 100 8 0 Y H522 38 100 0 4 N — 78 6.3 34 0 Y H23, H522, OVCAR 3,SF29 79 6.3 26 6 N — 86 6.3 38 0 Y OVCAR 3, OVCAR 5, H522 87 25 30 2 YH522 12 3.1 26 4 Y H522, MDA-MB-435 93 25 22 8 Y OVCAR-3 94 50 22 2 YCOLO205, OVCAR-3, H522 103 6.3 38 6 Y OVCAR 3, OVCAR 5, H522,MDA-MB-435, SF295 109 400 18 10 Y H522 112 50 18 2 Y OVCAR-3 113 200 184 Y H23, H522, OVCAR-3 110 50 14 0 Y OVCAR-3 124 25 28 0 Y H23, H522,OVCAR-3 MDA-MB-435

[1649] The following data in Table 9 summarize the in vivo properties ofseveral compounds of the current invention. The protocol for theexperiment is as follows. The dose-range finding study consists of fourgroups of three athymic mice each (four dose levels.) The compound isadministered on the basis of individual animal body weight. The route isintraperitoneal (IP) and the treatment schedule is daily for 14 days(qd×14) or once every 4 days for 12 days (q4d×3). The mice were observedfor survival, and body weights recorded weekly.

[1650] The efficacy study consists of three compound-treated groups (sixmice/group), a positive control-treated group (six mice), and avehicle-treated control group of 12 mice. Test compounds wereadministered IP under the treatment schedules listed above (qd×14 orq4d×3), whereas the positive control agent (Taxol) was administeredintravenously (IV) at a dosage level of 15 mg/kg/dose for fiveconsecutive days (qd×5). All agents were administered on the basis ofindividual animal body weight. Treatment began when the implanted tumorswere approximately 100 mg in size (range of 65 to 200 mg). The mice wereobserved daily for survival. Each tumor was measured by caliper in twodimensions and converted to tumor mass using the formula for a prolateellipsoid (a×b²/2) and assuming unit density. Tumor measurements andanimal body weights were recorded twice weekly. Antitumor activity wasassessed by the delay in tumor growth of the treated groups incomparison to the vehicle-treated control group, partial and completeregressions, and tumor-free survivors. TABLE 9 In Vivo Evaluation ofSeveral Compounds of the Current Invention. Tumor Compound Dose (mg/kg)Route Schedule free/total T-C (days) 78 0.5 IP  qd × 14 0/6 0.8 78 0.33IP  qd × 14 0/6 1.8 78 0.22 IP  qd × 14 0/6 −0.8 78 1.5 IP q4d × 3 0/62.5 78 1.0 IP q4d × 3 0/6 1.1 78 0.67 IP q4d × 3 0/6 2.0 12 0.6 IP q4d ×3 0/6 0.3 12 0.4 IP q4d × 3 0/6 0.2 12 0.27 IP q4d × 3 0/6 1.2 87 15 IPq4d × 3 0/6 2.5 87 10 IP q4d × 3 0/6 2.9 87 6.7 IP q4d × 3 0/6 1.4

[1651] Although the invention has been described in detail for thepurpose of illustration, it is understood that such detail is solely forthat purpose, and variations can be made therein by those skilled in theart without departing from the spirit and scope of the invention whichis defined by the following claims.

What is claimed:
 1. A compound of the following formula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂-(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; the combination of X, D, and Q are either: D=Q=N and X=CH; orD=X=N and Q=CH; or Q=X=N and D=CH; or Q=N and D=X=CH; V=NH; O; S; orCH₂; R₂=phenyl; substituted phenyl, wherein the substituents (1-2 innumber) are in any position and are independently selected from thegroup consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃,NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, andC(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl; heterocycles selected from thegroup consisting of: 2-pyridyl; 3-pyridyl; 4-pyridyl; 2-pyrimidyl;4-pyrimidyl; 5-pyrimidyl; thiophene-2-yl; thiophene-3-yl; 2-furanyl;3-furanyl; oxazol-2-yl; oxazol-4-yl; oxazol-5-yl; thiazol-2-yl;thiazol-4-yl; thiazol-5-yl; imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl;pyrazol-4-yl; isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl;isothiazol-3-yl; isothiazol-4-yl; isothiazol-5-yl;1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl; benzo[b]thiophene-2-yl;2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl; pyrazin-2-yl;pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl; 3-quinolinyl;4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and 4-isoquinolinyl; orsubstituted heterocycle, wherein the substituents (1-2 in number) are inany position and are independently selected from the group consisting ofBr, Cl, F, R₁, and C(O)CH₃; R₃ are the same or different andindependently selected from the group consisting of: H; C₁-C₄-straightchain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenyl chain;(CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₄=H; C₁-C₄-straight chainalkyl; or C₃-C₄-branched chain alkyl; R₃ and R₄ can be linked togetherby a carbon chain to form with intervening atoms a 5-8-memberedsaturated or unsaturated ring; n₁=0-3; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃;OCH₂CH₂; or CHCH₃; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)C(O)R₅;N(R₁)C(O)CH(R₆)NH₂; N(R₁)SO₂R₃; N(R₁)C(O)NHR₃; or N(R₁)C(O)OR₆;R₅=C₃-C₇-cycloalkyl; R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chainalkyl; C₂-C₄-alkenyl chain; (CH₂)_(n)Ph; or (CH₂)_(n)-substitutedphenyl, wherein the phenyl substituents are as defined above in R₂; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein R₃ are the same or different and independently selectedfrom the group consisting of: H; C₁-C₄-straight chain alkyl; andC₃-C₄-branched chain alkyl; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)SO₂R₃;or N(R₁)C(O)NHR₃.
 3. A compound according to claim 1, wherein two of X,D, and Q=N; R₃ are the same or different and independently selected fromthe group consisting of: H; C₁-C₄-straight chain alkyl; andC₃-C₄-branched chain alkyl; Y=H; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)SO₂R₃; orN(R₁)C(O)NHR₃; or a pharmaceutically acceptable salt thereof.
 4. Acompound of the following formula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; the combination of X, D, and Q are either: D=Q=N and X=CH; orD=X=N and Q=CH; or Q=X=N and D=CH; or Q=N and D=X=CH; V=NH; O; S; orCH₂; R₂=phenyl; substituted phenyl, wherein the substituents (1-2 innumber) are in any position and are independently selected from thegroup consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃,NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, andC(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl; heterocycles selected from thegroup consisting of: 2-pyridyl; 3-pyridyl; 4-pyridyl; 2-pyrimidyl;4-pyrimidyl; 5-pyrimidyl; thiophene-2-yl; thiophene-3-yl; 2-furanyl;3-furanyl; oxazol-2-yl; oxazol-4-yl; oxazol-5-yl; thiazol-2-yl;thiazol-4-yl; thiazol-5-yl; imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl;pyrazol-4-yl; isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl;isothiazol-3-yl; isothiazol-4-yl; isothiazol-5-yl;1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl; benzo[b]thiophene-2-yl;2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl; pyrazin-2-yl;pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl; 3-quinolinyl;4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and 4-isoquinolinyl; orsubstituted heterocycle, wherein the substituents (1-2 in number) are inany position and are independently selected from the group consisting ofBr, Cl, F, R₁, and C(O)CH₃; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃; OCH₂CH₂; orCHCH₃; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)C(O)R₅; N(R₁)C(O)CH(R₆)NH₂;N(R₁)SO₂R₃; N(R₁)C(O)NHR₃; or N(R₁)C(O)OR₆; R₃ are the same or differentand independently selected from the group consisting of: H;C₁-C₄-straight chain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenylchain; (CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₅=C₃-C₇-cycloalkyl;R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chain alkyl; orC₂-C₄-alkenyl chain; or a pharmaceutically acceptable salt thereof.
 5. Acompound according to claim 4, wherein two of X, D, and Q=N.
 6. A methodof treating a mammal with a disorder mediated by elevated levels of cellproliferation compared to a healthy mammal comprising: administering atherapeutically effective amount of the compound of claim 1 to themammal under conditions effective to treat the disorder mediated byelevated levels of cell proliferation compared to a healthy mammal. 7.The method of claim 6, wherein the disorder mediated by elevated levelsof cell proliferation compared to a healthy mammal is cancer, whereinthe cancer is selected from the group consisting of breast cancer, coloncancer, central nervous system cancer, leukemia, melanoma, lung cancer,ovarian cancer, prostate cancer, and renal cancer.
 8. The method ofclaim 7, wherein the disorder mediated by elevated levels of cellproliferation compared to a healthy mammal is restenosis.
 9. The methodof claim 7, wherein the mammal is human.
 10. A pharmaceuticalcomposition of matter comprising the compound of claim 1 and one or morepharmaceutical excipients.
 11. A method of treating a mammal with adisorder mediated by elevated levels of cell proliferation compared to ahealthy mammal comprising: administering a therapeutically effectiveamount of the compound of claim 4 to the mammal under conditionseffective to treat the disorder mediated by elevated levels of cellproliferation compared to a healthy mammal.
 12. The method of claim 11,wherein the disorder mediated by elevated levels of cell proliferationcompared to a healthy mammal is cancer, wherein the cancer is selectedfrom the group consisting of breast cancer, colon cancer, centralnervous system cancer, leukemia, melanoma, lung cancer, ovarian cancer,prostate cancer, and renal cancer.
 13. The method of claim 11, whereinthe disorder mediated by elevated levels of cell proliferation comparedto a healthy mammal is restenosis.
 14. The method of claim 11, whereinthe mammal is human.
 15. A pharmaceutical composition of mattercomprising the compound of claim 4 and one or more pharmaceuticalexcipients.
 16. A process for preparation of a purine derivativecompound of the formula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; the combination of X, D, and Q are either: D=Q=N, and X=CH; orD=X=N, and Q=CH; or Q=X=N, and D=CH; or Q=N, and D=X=CH; V=NH; O; S; orCH₂; R₂=phenyl; substituted phenyl, wherein the substituents (1-2 innumber) are in any position and are independently selected from thegroup consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃,NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, andC(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl; heterocycles selected from thegroup consisting of: 2-pyridyl; 3-pyridyl; 4-pyridyl; 2-pyrimidyl;4-pyrimidyl; 5-pyrimidyl; thiophene-2-yl; thiophene-3-yl; 2-furanyl;3-furanyl; oxazol-2-yl; oxazol-4-yl; oxazol-5-yl; thiazol-2-yl;thiazol-4-yl; thiazol-5-yl; imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl;pyrazol-4-yl; isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl;isothiazol-3-yl; isothiazol-4-yl; isothiazol-5-yl;1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl; benzo[b]thiophene-2-yl;2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl; pyrazin-2-yl;pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl; 3-quinolinyl;4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and 4-isoquinolinyl; orsubstituted heterocycle, wherein the substituents (1-2 in number) are inany position and are independently selected from the group consisting ofBr, Cl, F, R₁, and C(O)CH₃; R₃ are the same or different andindependently selected from the group consisting of: H; C₁-C₄-straightchain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenyl chain;(CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₄=H; C₁-C₄-straight chainalkyl; or C₃-C₄-branched chain alkyl; R₃ and R₄ can be linked togetherby a carbon chain to form with intervening atoms a 5-8-memberedsaturated or unsaturated ring; n₁=0-3; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃;OCH₂CH₂; or CHCH₃; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)C(O)R₅;N(R₁)C(O)CH(R₆)NH₂; N(R₁)SO₂R₃; N(R₁)C(O)NHR₃; or N(R₁)C(O)OR₆;R₅=C₃-C₇-cycloalkyl; R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chainalkyl; C₂-C₄-alkenyl chain; (CH₂)_(n)Ph; or (CH₂)_(n)-substitutedphenyl, wherein the phenyl substituents are as defined above in R₂; or apharmaceutically acceptable salt thereof; said process comprising:reacting a first intermediate compound of the formula:

where Z=Br or I with a compound of the formula: R₂—B(OH)₂, R₂—Sn(n-Bu)₃,or R₂—Sn(Me)₃, or mixtures thereof, under conditions effective to formthe purine derivative compound.
 17. A process according to claim 16,wherein if Y is NHR₁, said process further comprises: reacting thepurine derivative compound with R₃C(O)Cl or R₅C(O)Cl or R₃SO₂Cl or R₃NCOor R₆OC(O)Cl under conditions effective to form a final product havingthe same formula as the purine derivative compound except that Y isNR₁C(O)R₃ or NR₁C(O)R₅ or NR₁SO₂R₃ or NR₁C(O)NHR₃ or NR₁C(O)OR₆.
 18. Aprocess according to claim 16 further comprising: reacting a secondintermediate compound of the formula:

with a second compound of the formula:

wherein: V₁=NH₂; OH; SH; under conditions effective to form the firstintermediate compound.
 19. A process according to claim 18 furthercomprising: reacting a third intermediate compound of the formula:

with a compound of the formula R₁-Z under conditions effective to formthe second intermediate compound.
 20. A process according to claim 16,wherein the purine derivative compound has the formula:


21. A process for preparation of a purine derivative compound of theformula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; the combination of X, D, and Q are either: D=Q=N, and X=CH; orD=X=N, and Q=CH; or Q=X=N, and D=CH; or Q=N, and D=X=CH; V=NH; O; S; orCH₂; R₂=phenyl; substituted phenyl, wherein the substituents (1-2 innumber) are in any position and are independently selected from thegroup consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃,NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, andC(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl; heterocycles selected from thegroup consisting of: 2-pyridyl; 3-pyridyl; 4-pyridyl; 2-pyrimidyl;4-pyrimidyl; 5-pyrimidyl; thiophene-2-yl; thiophene-3-yl; 2-furanyl;3-furanyl; oxazol-2-yl; oxazol-4-yl; oxazol-5-yl; thiazol-2-yl;thiazol-4-yl; thiazol-5-yl; imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl;pyrazol-4-yl; isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl;isothiazol-3-yl; isothiazol-4-yl; isothiazol-5-yl;1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl; benzo[b]thiophene-2-yl;2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl; pyrazin-2-yl;pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl; 3-quinolinyl;4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and 4-isoquinolinyl; orsubstituted heterocycle, wherein the substituents (1-2 in number) are inany position and are independently selected from the group consisting ofBr, Cl, F, R₁, and C(O)CH₃; R₃ are the same or different andindependently selected from the group consisting of: H; C₁-C₄-straightchain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenyl chain;(CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₄=H; C₁-C₄-straight chainalkyl; or C₃-C₄-branched chain alkyl; R₃ and R₄ can be linked togetherby a carbon chain to form with intervening atoms a 5-8-memberedsaturated or unsaturated ring; n₁=0-3; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃;OCH₂CH₂; CHCH₃; Y=H; OR_(1;) N(R₁)₂; N(R₁)C(O)R₃; N(R₁)C(O)R₅;N(R₁)C(O)CH(R₆)NH₂; N(R₁)SO₂R₃; N(R₁)C(O)NHR₃; or N(R₁)C(O)OR₆;R₅=C₃-C₇-cycloalkyl; R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chainalkyl; C₂-C₄-alkenyl chain; (CH₂)_(n)Ph; or (CH₂)_(n)-substitutedphenyl, wherein the phenyl substituents are as defined above in R₂; or apharmaceutically acceptable salt thereof, said process comprising:reacting a first intermediate compound of the formula:

under reductive or hydrogenation conditions effective to form the purinederivative compound.
 22. A process according to claim 21 furthercomprising: reacting a second intermediate compound of the formula:

with a second compound of the formula:

under conditions effective to form the first intermediate compound. 23.A process according to claim 22 further comprising: reacting a thirdintermediate compound of the formula:

with a compound of the formula: R₂—B(OH)₂, R₂—Sn(n-Bu)₃, or R₂—Sn(Me)₃,or mixtures thereof, under conditions effective to form the secondintermediate compound.
 24. A process according to claim 21 furthercomprising: reacting a fourth intermediate compound of the formula:

with a compound of the formula: R₂—B(OH)₂, R₂—Sn(n-Bu)₃, or R₂—Sn(Me)₃,or mixtures thereof, under conditions effective to form the firstintermediate compound.
 25. A process according to claim 24 furthercomprising: reacting a fifth intermediate compound of the formula:

with a compound of the formula:

under conditions effective to form the fourth intermediate compound. 26.A process according to claim 21, wherein the purine derivative compoundhas the formula:


27. A process for preparation of a purine derivative compound of theformula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; the combination of X, D, and Q are either: D=Q=N, and X=CH; orD=X=N, and Q=CH; or Q=X=N, and D=CH; or Q=N, and D=X=CH; V=NH; O; S; orCH₂; R₂=phenyl; substituted phenyl, wherein the substituents (1-2 innumber) are in any position and are independently selected from thegroup consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃,NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, andC(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl; heterocycles selected from thegroup consisting of: 2-pyridyl; 3-pyridyl; 4-pyridyl; 2-pyrimidyl;4-pyrimidyl; 5-pyrimidyl; thiophene-2-yl; thiophene-3-yl; 2-furanyl;3-furanyl; oxazol-2-yl; oxazol-4-yl; oxazol-5-yl; thiazol-2-yl;thiazol-4-yl; thiazol-5-yl; imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl;pyrazol-4-yl; isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl;isothiazol-3-yl; isothiazol-4-yl; isothiazol-5-yl;1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl; benzo[b]thiophene-2-yl;2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl; pyrazin-2-yl;pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl; 3-quinolinyl;4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and 4-isoquinolinyl; orsubstituted heterocycle, wherein the substituents (1-2 in number) are inany position and are independently selected from the group consisting ofBr, Cl, F, R₁, and C(O)CH₃; R₃ are the same or different andindependently selected from the group consisting of: H; C₁-C₄-straightchain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenyl chain;(CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₄=H; C₁-C₄-straight chainalkyl; or C₃-C₄-branched chain alkyl; R₃ and R₄ can be linked togetherby a carbon chain to form with intervening atoms a 5-8-memberedsaturated or unsaturated ring; n₁=0-3; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃;OCH₂CH₂; or CHCH₃; Y=H; OR₁; N(R₁)₂; N(R₁)C(O)R₃; N(R₁)C(O)R₅;N(R₁)C(O)CH(R₆)NH₂; N(R₁)SO₂R₃; N(R₁)C(O)NHR₃; or N(R₁)C(O)OR₆;R₅=C₃-C₇-cycloalkyl; R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chainalkyl; C₂-C₄-alkenyl chain; (CH₂)_(n)Ph; or (CH₂)_(n)-substitutedphenyl, wherein the phenyl substituents are as defined above in R₂; or apharmaceutically acceptable salt thereof; said process comprising:reacting a first intermediate compound of the formula:

with a compound of the formula:

where V₁=NH₂; OH; or SH; under conditions effective to form the purinederivative compound.
 28. A process according to claim 27, wherein if Yis NHR₁, said process further comprises: reacting the purine derivativecompound with R₃C(O)Cl or R₅C(O)Cl or R₃SO₂Cl or R₃NCO or R₆OC(O)Clunder conditions effective to form a final product having the sameformula as the purine derivative compound except that Y is NR₁C(O)R₃ orNR₁C(O)R₅ or NR₁SO₂R₃ or NR₁C(O)NHR₃ or NR₁C(O)OR₆.
 29. A processaccording to claim 27 further comprising: reacting a second intermediatecompound of the formula:

with a compound of the formula R₁-Z under conditions effective to formthe first intermediate compound.
 30. A process according to claim 29further comprising: reacting a third intermediate compound of theformula:

with a compound of the formula 2,6-dichloropurine (Formula IV) underconditions effective to form the second intermediate compound.
 31. Aprocess according to claim 30 further comprising: reacting a fourthintermediate compound of the formula:

with a compound of the formula: R₂—B(OH)₂, R₂—Sn(n-Bu)₃, or R₂—Sn(Me)₃,or mixtures thereof, under conditions effective to form the thirdintermediate compound.
 32. A process according to claim 28, wherein thepurine derivative compound has the formula:


33. A process for preparation of a purine derivative compound of theformula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; the combination of X, D, and Q are either: D=Q=N and X=CH; orD=X=N and Q=CH; or Q=X=N and D=CH; or Q=N and D=X=CH; V=NH; O; S; orCH₂; R₂=phenyl; substituted phenyl, wherein the substituents (1-2 innumber) are in any position and are independently selected from thegroup consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃,NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, andC(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl; heterocycles selected from thegroup consisting of: 2-pyridyl; 3-pyridyl; 4-pyridyl; 2-pyrimidyl;4-pyrimidyl; 5-pyrimidyl; thiophene-2-yl; thiophene-3-yl; 2-furanyl;3-furanyl; oxazol-2-yl; oxazol-4-yl; oxazol-5-yl; thiazol-2-yl;thiazol-4-yl; thiazol-5-yl; imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl;pyrazol-4-yl; isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl;isothiazol-3-yl; isothiazol-4-yl; isothiazol-5-yl;1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl; benzo[b]thiophene-2-yl;2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl; pyrazin-2-yl;pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl; 3-quinolinyl;4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and 4-isoquinolinyl; orsubstituted heterocycle, wherein the substituents (1-2 in number) are inany position and are independently selected from the group consisting ofBr, Cl, F, R₁, and C(O)CH₃; R₃ are the same or different andindependently selected from the group consisting of: H; C₁-C₄-straightchain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenyl chain;(CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₄=H; C₁-C₄-straight chainalkyl; or C₃-C₄-branched chain alkyl; R₃ and R₄ can be linked togetherby a carbon chain to form with intervening atoms a 5-8-memberedsaturated or unsaturated ring; n₁=0-3; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃;OCH₂CH₂; or CHCH₃; Y=NR₁C(O)R₃; NR₁SO₂R₃; NR₁C(O)NHR₃;or NR₁C(O)OR₆R₅=C₃-C₇-cycloalkyl; R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chainalkyl; C₂-C₄-alkenyl chain; (CH₂)_(n)Ph; or (CH₂)_(n)-substitutedphenyl, wherein the phenyl substituents are as defined above in R₂; or apharmaceutically acceptable salt thereof; said process comprising:reacting a first intermediate compound having the same formula as thepurine derivative compound except that Y=NHR₁, with R₃COCl or R₅COCl orR₃SO₂Cl or R₃NCO or R₆OC(O)Cl under conditions effective to form thepurine derivative compound.
 34. A process according to claim 33 furthercomprising: reacting a second intermediate compound having the sameformula as the first intermediate compound except that Y is NH₂, withR₈CH₂Z or R₈CHO under conditions effective to form the firstintermediate compound where Y=NHR₁ or N(R₁)₂, wherein Z is Br or I andR₈=C₁-C₅-straight chain alkyl; C₂-C₅-straight alkenyl chain;C₃-C₅-branched alkyl chain; C₃-C₅-branched alkenyl chain;C₃-C₇-cycloalkyl; CF₃; CH₂CF₃.
 35. A process for preparation of a purinederivative compound of the formula:

wherein: R₁ are the same or different and independently selected fromthe group consisting of: H; C₁-C₆-straight chain alkyl; C₂-C₆-straightalkenyl chain; C₃-C₆-branched alkyl chain; C₃-C₆-branched alkenyl chain;C₃-C₇-cycloalkyl; CH₂—(C₃-C₇-cycloalkyl); CH₂CF₃; CH₂CH₂CF₃; andCH(CF₃)₂; the combination of X, D, and Q are either: D=Q=N and X=CH; orD=X=N and Q=CH; or Q=X=N and D=CH; or Q=N and D=X=CH; V=NH; O; S; orCH₂; R₂=phenyl; substituted phenyl, wherein the substituents (1-2 innumber) are in any position and are independently selected from thegroup consisting of R₁, OR₁, SR₁, S(O)R₁, S(O₂)R₁, NHR₁, NO₂, OC(O)CH₃,NHC(O)CH₃, F, Cl, Br, CF₃, C(O)R₁, C(O)NHR₁, phenyl, andC(O)NHCHR₁CH₂OH; 1-naphthyl; 2-naphthyl; heterocycles selected from thegroup consisting of: 2-pyridyl; 3-pyridyl; 4-pyridyl; 2-pyrimidyl;4-pyrimidyl; 5-pyrimidyl; thiophene-2-yl; thiophene-3-yl; 2-furanyl;3-furanyl; oxazol-2-yl; oxazol-4-yl; oxazol-5-yl; thiazol-2-yl;thiazol-4-yl; thiazol-5-yl; imidazol-2-yl; imidazol-4-yl; pyrazol-3-yl;pyrazol-4-yl; isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl;isothiazol-3-yl; isothiazol-4-yl; isothiazol-5-yl;1,3,4-thiadiazol-2-yl; benzo[b]furan-2-yl; benzo[b]thiophene-2-yl;2-pyrrolyl; 3-pyrrolyl; 1,3,5-triazin-2-yl; pyrazin-2-yl;pyridazin-3-yl; pyridazin-4-yl; 2-quinolinyl; 3-quinolinyl;4-quinolinyl; 1-isoquinolinyl; 3-isoquinolinyl; and 4-isoquinolinyl; orsubstituted heterocycle, wherein the substituents (1-2 in number) are inany position and are independently selected from the group consisting ofBr, Cl, F, R₁, and C(O)CH₃; R₃ are the same or different andindependently selected from the group consisting of: H; C₁-C₄-straightchain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenyl chain;(CH₂)_(n)Ph; and (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; R₄=H; C₁-C₄-straight chainalkyl; or C₃-C₄-branched chain alkyl; R₃ and R₄ can be linked togetherby a carbon chain to form with intervening atoms a 5-8-memberedsaturated or unsaturated ring; n₁=0-3; n=0-3; A=CH₂; (CH₂)₂; (CH₂)₃;OCH₂CH₂; or CHCH₃; Y=NHC(O)CH(R₆)NH₂; R₅=C₃-C₇-cycloalkyl;R₆=C₁-C₄-straight chain alkyl; C₃-C₄-branched chain alkyl; C₂-C₄-alkenylchain; (CH₂)_(n)Ph; or (CH₂)_(n)-substituted phenyl, wherein the phenylsubstituents are as defined above in R₂; or a pharmaceuticallyacceptable salt thereof; said process comprising: reacting a firstintermediate compound having the same formula as the purine derivativecompound except that Y is NH₂, with a compound of the formula:PNHCH(R₆)CO₂H under conditions effective to form the purine derivativecompound after a suitable deprotection strategy, wherein P=C(O)OtBu;C(O)OCH₂Ph; Fmoc Benzyl; or Alloc.